PHARMACEUTICAL SERVICES PROGRAMME MINISTRY OF HEALTH MALAYSIA
VOLUME 1 2018
PHARMACY RESEARCH REPORTS
PHARMACY RESEARCH REPORTS VOLUME 1 2018
The Pharmacy Research Reports is published by the Pharmaceutical Services Programme, Ministry of Health Malaysia (MOH). This is an International Standard Serial Number (ISSN) registered publication with the National Bibliography Centre, National Library of Malaysia. This document contains compilation of research articles of pharmacy related researches conducted in the MOH by the MOH pharmacists and other professionals. All researches included in this report were registered with the National Medical Research Register (NMRR) and ethics approvals had been obtained from the Medical Research and Ethics Committee (MREC) if required. The opinions expressed in all articles, including the Editorials, are the authors’ own and do not necessarily reflect the view of the Pharmaceutical Services Programme, Ministry of Health Malaysia.
December 2018 © Ministry of Health Malaysia
Editorial Address: Editor in Chief Pharmacy Research Reports Pharmacy Policy and Strategic Planning Division Pharmaceutical Services Programme Ministry of Health Malaysia Lot 36, Jalan Universiti, 46200 Petaling Jaya, Selangor, Malaysia Tel. : (603) 7841 3200 Fax : (603) 7968 2222 Website : https://www.pharmacy.gov.my
PHARMACY RESEARCH REPORTS
VOLUME 1 2018
EDITORIAL BOARD
Advisors
Dr Hasenah Ali & MOH Pharmacy Research and Development (R&D) Committee
Editor in Chief
Dr. Abdul Haniff Mohd Yahaya
Reviews Editor
Dr. Azuana Ramli
Mary Chok Chiew Fong
Ho See Wan
Chan Lai Yue
Nurhafiza Md Hamzah
Secretariat
Dr. Azuana Ramli
Chan Pui Lim 3
Ho See Wan
Safura Sa’ad
Noor Atiqah Mat Yusoff
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MEMBERS OF THE MOH PHARMACY RESEARCH AND DEVELOPMENT (R&D) COMMITTEE 2017-2018
Chairperson Dr. Hasenah binti Ali Director of Pharmacy Policy and Strategic Planning Division Secretary Dr. Azuana binti Ramli Deputy Director, Pharmacy Policy and Strategic Planning Division Committee Members Mazlan bin Ismail Norazlin binti Abd. Kadir Pharmacy Enforcement Division Pharmacy Practice and Development Division Ida Syazrina binti Ibrahim Bibi Faridha binti Mohd Salleh National Pharmaceutical Regulatory Agency Pharmacy Policy and Strategic Planning Division Dzafarullah bin Daud Zahrina binti Abdul Kadir Pharmacy Board Malaysia Johor State Health Department Norazila binti Abd. Ghani Nazmi Liana binti Azmi Hospital Sultanah Bahiyah, Kedah Hospital Raja Perempuan Zainab II, Kelantan Saidatul Raihan binti Ibrahim Basariah binti Naina Hospital Melaka Hospital Tuanku Ja’afar, Negeri Sembilan Dr. Jannatul Ain binti Jamal Rohaizan binti Mohd Hanafiah Hospital Tengku Ampuan Afzan, Pahang Pulau Pinang State Health Department Dr. Abdul Haniff bin Mohd Yahaya Hazlin Syafinar binti Hussein Hospital Teluk Intan, Perak Perlis State Health Department Norharlina binti Sulaiman Aishah binti Hamzah Klang District Health Office, Selangor Hospital Hulu Terengganu, Terengganu Jerry Liew Ee Siung Ridhwan bin Abdullah Hospital Queen Elizabeth, Sabah Hospital Sentosa, Sarawak Soo Bee Kuan Yuzlina binti Mohd Yahaya Labuan State Health Department Hospital Rehabilitasi Cheras, Kuala Lumpur Dr. Norkasihan binti Ibrahim Azmi Nor Mohd Farez bin Ahmat Hospital Kuala Lumpur National Cancer Institute Secretariat Chan Pui Lim Mary Chok Chiew Fong Pharmacy Policy and Strategic Planning Division Pharmacy Policy and Strategic Planning Division 4 Ho See Wan Chan Lai Yue Pharmacy Policy and Strategic Planning Division Pharmacy Policy and Strategic Planning Division Safura binti Sa’ad Noor Atiqah binti Mat Yusoff Pharmacy Policy and Strategic Planning Division Pharmacy Policy and Strategic Planning Division Mohd Faiz bin Abdul Manan
Pharmacy Policy and Strategic Planning Division
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FOREWORD Senior Director of Pharmaceutical Services
It is with great pleasure that I introduce you to the first Pharmacy Research Reports published by the Pharmaceutical Services Programme. This report, the Pharmacy Research Reports Volume 1 2018, marks a milestone in our effort to document research findings conducted by the pharmacists in the Ministry of Health. This sharing of information is hoped to enable pharmacists in the country to utilise available research findings in their practices and to encourage more pharmacists to embark in pharmacy research.
I would like to take this opportunity to thank all the researchers who have agreed to share their research findings through this inaugural report for the benefit of the pharmacy services. It demonstrates their hard work and dedication in striving for improvements. Despite their challenging and busy schedule they are willing to take the time to document their research for the benefit of pharmacy services and the population as a whole.
With this, I would like to express my gratitude for all the efforts put in by the Editor in Chief, the reviewers and the editorial committee members to make the first publication of the Pharmacy Research Reports a success.
Thank you.
5
Dr. Ramli Bin Zainal, RPh. 1045 Senior Director of Pharmaceutical Services Ministry of Health Malaysia
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EDITORIAL
From Research to Practice
Abdul Haniff Mohd Yahaya
Research is an essential part of pharmaceutical services and healthcare delivery. It is encouraging to note that the culture of conducting research is getting stronger among fellow pharmacists in the Ministry of Health Malaysia (MOH). Research is fundamental to generate evidences that support policy decision-making and improve health services. As part of the efforts to enhance research and knowledge sharing, as stipulated in the Pharmacy Programme Strategic Plan 2017-2020, we are honoured to present to all our readers the Pharmacy Research Reports Volume 1 2018.
This report encompasses research findings in various areas such as quality use of medicines, impact of pharmacy services, policy research, clinical research, pharmacoepidemiology and drug safety. We believe that the documentation of research evidence is an important step to enable translation of research findings into policy and practice. This platform is also intended to introduce researchers from different fields and to gather researchers with similar interests to initiate bigger and more impactful research projects, avoiding duplicative efforts at different facilities. It is hoped that the research findings published are able to help policy decisions making and subsequently drive new policies for the continuous strengthening of the health system.
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CONTENTS page i. Foreword by the Senior Director of Pharmaceutical Services 5 ii. EDITORIAL 6
1. Availability of Essential Medicines in the Remote Public Health Facilities in Malaysia 8 Izzati Mohd Farok, Bibi Faridha Mohd Salleh, Lau Ling Wei, Ramli Zainal 2. Adverse Drug Reactions of Clozapine and Their Management in a Tertiary Care Hospital in 15 Kelantan Nazmi Liana Azmi, Fazlina Mohamed, Nurul Khairiyah Wanik, Chua Siew May, Nur ‘Izzati Ahmad Zawawi 3. A Prospective Study on Antibiotic De-escalation Practice in the Medical Wards of Penang 24 General Hospital Wong Kar Loon, Wong Mei Ling, Chong Zan Kai, Siva Malar Ganasen, Wan Sakinah Wan Hasbullah, Chee Sze Hui, Chow Ting Soo, Leong Kar Nim, Wong Peng Shyan, Ch’ng Wei Choong 4. The Impact of Epilepsy Review Service on Seizure Control in Primary Care 32 Wong Su Li, Cheang Ching Ye, Norharlina Sulaiman, Hanum Maisarah Abdul Rahman, Ng Kar Mun 5. Evaluation of Utilisation and Concordance to Guideline-recommended Statin Therapy at 42 Medical Outpatient Clinic, Hospital Kuala Krai Low Joo Zheng, Ahmad Salihin Abdullah, Nurul Azerah Idris, Siti Noriah Muhd Yuna, M. Irfan Ab Aziz 6. Retrospective Review of Postnatal Growth Rate of Premature Infants Receiving Early 52 Parenteral Nutrition in a Malaysian Tertiary Hospital Neonatal Intensive Care Unit Loo Jing Hean, Limata @ Monalita Binti Othman 7. Knowledge and Attitude on Safe Handling of Cytotoxic Agents among Healthcare Staff in 61 Tengku Ampuan Rahimah Hospital (HTAR), Klang Lee Jian Lynn, Tai Chu Hong, Lim Soon Seng, Keng Zhi Hong, Nur Syuhada Zainudin, Yeo Wei Yan, Lee Sheah Lin, Khairul Azrul Abdul Rahman 8. Scheduled Substances as a Cause Leading to Dangerous Drug Abuse 67 Zamrul Hisyam Noor, Ahmad Aizat Zaini, Mohd Hanif Mustafa 9. Study of Traditional and Complementary Medicine (TCM) Usage among Cancer Patients 78
Receiving Chemotherapy in Hospital Melaka 7 Wong Kuo Zang, Mastria Mohamed, Loh Wan Ting, Suhadah Ahad 10. Comparing the Glycaemic and Weight Control Effects of Basal-bolus and Premixed Insulin 87 Regimen among Patients with Type 2 Diabetes Mellitus in Johor Chong Men Yee 11. Patients’ Beliefs about Generic Medicines in the Outpatient Setting, Sibu Hospital 93 Chuo Sing Hong, Carmen Wong Jia Jia, Ling Mei Siew, Sia Khang Lin, Tiong Chang Hwa 12. Assessment of Public Knowledge and Perception towards Childhood Vaccination in Perlis, 104 Malaysia Wan Nor Amalina Zainun, Nuwairoh Nasir, Nur Iffah Iwani Ghazali, Tan Keh Ying
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Availability of Essential Medicines in the Remote Public Health Facilities
in Malaysia
Izzati Mohd Farok1, Bibi Faridha Mohd Salleh1, Lau Ling Wei1, Ramli Zainal2
1 Pharmacy Policy and Strategic Planning Division, Ministry of Health Malaysia 2 Pharmaceutical Services Programme, Ministry of Health Malaysia
Abstract
Introduction: Approximately one-third of the world population particularly in Africa and Asia lack consistent access to essential medicines. Providing access to medicines by ensuring availability of essential medicines is one of the objectives of a national medicine policy. Assessing the availability of essential medicines will help in understanding and identifying areas for improvement in the medicines distribution and stock management system. Objective: This study aimed to access the availability of essential medicines in remote health facilities in Malaysia. Methods: A retrospective cross-sectional survey covering 20 remote health facilities in four states (Selangor, Pahang, Johor and Sarawak) in Malaysia was conducted. A basket of drugs consisted of 10 highly utilised essential medicines listed in the Malaysian National Essential Medicine List was used to measure the availability, stockout days and time between order and delivery of the selected essential medicines. Result: On average, availability of the selected essential medicines at twenty remote health facilities was found to be more than 95%. Average medicines stockout days in the four states ranged from 0 to 12 days. At the same time, the study found that the average days between order and delivery of the medicines in the four states were between 6 to 13 days. Conclusion: Availability of essential medicines in the rural health facilities was high (above 95%) and is in line with the recommendations from World Health Organisation (WHO) of 80% availability of essential medicines to ensure equitable access and rational use of medicines. It is recommended that an in-depth study is performed to look into the factors contributing to the medicines stockout and delays in medicines delivery in Malaysia.
Keywords: delivery time, essential medicines, medicines access, medicines availability, stockouts, remote facilities, Malaysia
NMRR ID: NMRR-17-2679-39128 8
Corresponding author: Izzati Mohd Farok Pharmacy Policy and Strategic Planning Division, Ministry of Health Malaysia. Lot 36, Jalan Universiti, 46200 Petaling Jaya, Selangor. Email: [email protected]
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Introduction Essential medicines are medicines that fulfil the healthcare needs of a population. These medicines should be available within the health systems at all times to ensure continuous access to safe, good quality and affordable medicines1. As reported by World Health Organization (WHO), one-third of the global population do not have regular access to essential medicines. It is estimated that more than 50% of the population in some of the lowest-income countries such as in Africa and Asia have no regular access to essential medicines2. Low availability of essential medicines in the public sector is often caused by a lack of public resources due to underfunding or under-budgeting, inaccurate demand forecasting, and inefficient public sector procurement and distribution of medicines3. In Malaysia, the importance of essential medicines is emphasised in the Malaysian National Medicines Policy (MNMP). The MNMP promotes the availability of drugs through appropriate selection of medicines, improvement in the management of medicines procurement and the supply chain network, and through optimal utilisation of available financial resources to ensure sustainability of the healthcare system. The goal of the MNMP is to promote equitable access and rational use of safe, effective and affordable essential medicines of good quality to improve health outcomes for the people4. A study carried out by Kamaruzaman et al. in 2005 reported that although the average availability of essential medicines in Malaysia was high being more than 95%, the availability in certain areas in Sabah was less than 80%5. WHO sets the target in its medium-term strategic plan (2008- 2013) of which 80% of essential medicines should be available in all sectors to ensure equitable access and the rational use of medicines6. Availability of good quality, safe and affordable essential medicines may save lives, reduce suffering, and improve health with proper use. Insufficiencies in the supply and distribution of essential medicines may impair the effectiveness of care7. As recommended by WHO, process and outcome indicators (PR 27, PR 29 and OT 1) were collected to assess the effectiveness of the distribution system and the management of drugs at the local level and assess the attainment to make essential medicines available to the whole population in Malaysia9. The general aim of this report is to understand the performance of distribution system and efficacy of drug stock management in remote health facilities. Specifically, the objective is to measure the availability of essential medicines in remote health facilities in Malaysia.
Methods The methodology was adopted from the World Health Organization protocol - ‘Indicators for monitoring national drug policies – a practical manual, second edition, 19999.
Survey Design A cross-sectional survey was carried out at selected public health facilities. Data were retrospectively collected from existing records and inventory control documents for a period of 3 years, starting from January 2014 until December 2016. This research was registered with the National Medical Research 9 Register with NMRR identification number NMRR-17-2679-39128.
Survey Instrument Development Data collection forms were adopted from the WHO protocol9. Data collectors from the selected facilities were nominated and informed about the methodology and how to fill in the data collection forms to ensure consistency in results.
Sampling method and fielding Selection of facilities A multi-stage sampling method was used in this study. At the initial stage, cluster sampling of states was carried out according to the geographical regions of Malaysia. The 15 states in the country was 9 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 divided into five geographical regions: northern, middle, southern, eastern coastal and eastern. Four geographical regions were selected and one state was sampled from each region. The included states were Selangor (middle zone), Johor (southern zone), Pahang (eastern coastal zone), and Sarawak (eastern zone). The next stage involved systematic sampling of remote public health facilities in these four selected states using Microsoft Excel. The definition of remote health facility was a facility situated at a location of fewer than 100,000 inhabitants. A sample size of 20 remote public health facilities was adopted as recommended in the WHO protocol, considering of limitations in human and financial resources and logistical constraints. The list of remote public health facilities selected is as listed in Appendix 1.
Selection of medicines A basket of drugs consisted of 10 essential medicines was identified. These medicines are essential medicines listed in the Malaysian National Essential Medicine List and at the same time had high utilisation based on the Malaysia Statistics on Medicine 2010. The list of the ten medicines is enclosed in Appendix 2.
Definition of ordering, stock out and availability To measure the duration between order and delivery, term or major orderings were identified. Term or major ordering is a scheduled and consistent ordering of medicines according to the time period whereby the stocks can last for as defined by individual public health facilities. For staggered supplies of order, the percentage of the number of items and the quantity of each item received at the remote health facilities must be 80% and above. Stock out is defined as the period when the medicine is out of stock in the remote public health facility’s store. If medicine was available through a loan from other facilities, the medicine was still considered as out of stock from the store. Availability means the medicine is available at the remote health facilities on the day the survey was carried out.
Data collection, management, and analysis Official letters for data collection were sent to the participating facilities in Decembers during the study period. The data collection was conducted for a period of one month. Reminder calls were made to the respondents during this time. After receiving the completed forms, responses were reviewed and clarification was sought from the respondent if any information was unclear or missing. Three (3) indicators were measured. The first indicator was ‘Average time between order and delivery from central store to remote facilities’. The second indicator was ‘Average stock out duration for a basket of drugs in a sample of remote facilities’, and the third indicator was ‘Number of drugs from a basket of drugs available in a sample of remote health facilities’. Data were analysed as descriptive statistics using SPSS Version 20.
Results 10 Twenty (20) remote public health facilities in Malaysia were surveyed. These health facilities were situated at a distance of more than 100 kilometres from a town of 100,000 inhabitants. Table 1 showed that in Selangor, the average availability of a basket of drugs was found to be 100% in 2014 and dropped slightly to 96.7 % in 2015. It remained constant in 2016. In Pahang, the average availability of a basket of drugs improved remarkably from 98.3% to 100% in 2014 to 2015 but declined to 95% in 2016. In Johor, availability of drugs remained the same for the first two years but dropped 2.5% in 2016. In Sarawak’s remote public health facilities, 100% of a basket of drugs were available throughout the three years. The results in Table 2 showed that Sarawak and Pahang had a median of zero stock out duration for three consecutive years. Nevertheless, the stock out days ranged from a minimum of zero days to maximum of 43 days and a minimum of zero days to maximum of 141 days respectively. In 10 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018
Selangor, the median stock out days was zero in 2014 and remained zero in 2015 but increased slightly to 4 days in 2016. On the other hand, in Johor, the median stock out days increased from 2.5 days in 2014 to 14 days in 2015 and further rose to 16.5 days in 2016. Table 3 showed the average time between order and delivery from the central store to remote public health facilities from 2014 to 2016. In Selangor, the median average delivery time in 2014 was seven days and increased to eight days in 2015. In 2016, the median average delivery time decreased to six days with a maximum of 10 days. In Pahang, the median average delivery time was six days with a minimum of 1 day and a maximum of 32 days. As seen in the table, Johor’s remote public health facilities had a reduction of the median average delivery time from 11 days in 2014 to four days in 2016. Sarawak had the highest average delivery time. The remote public health facilities had a median delivery time of 13 days. Nevertheless, the average delivery time showed a reducing trend over the three years.
Table 1: Average percentage availability of a basket of drug in 20 remote public health facilities Average availability, % mean (SD), median (range) 2014 2015 2016 Average State 96.7 (5.8) 96.7 (5.8) 97.8 (4.4) Selangor 100 100 (90-100) 100 (90-100) 100 (90-100) 98.3 (4.1) 95(5.8) 97.7 (4.3) Pahang 100 100 (90-100) 95 (90-100) 100 (90-100) 97.5 (5) 97.5 (5) 95 (5.8) 96.7 (4.9) Johor 100 (90-100) 100 (90-100) 95 (90-100) 100 (90-100)
Sarawak 100 100 100 100 * SD – standard deviation
Table 2: Average stock out days of a basket of drugs in 20 remote public health facility stores Average stock out days, number of days mean (SD), median (range) 2014 2015 2016 Average State 9.6 (31.0) 7.4 (11.3) 13.0 (18.9) 10.0 (21.8) Selangor 0 (0-163) 0 (0-36) 4.0 (0-81) 0 (0-163) 4.5 (9.3) 12.1 (18.6) 10.5 (21.6) 9.0 (17.5) Pahang 0 (0-34) 0 (0-68) 0 (0-141) 0 (0-141) 11 12.0 (20.2) 18.9 (24.2) 27.1 (27.9) 19.4 (24.9) Johor 2.5 (0-73) 14.0 (0-96) 16.5 (0-87) 11.5 (0-96) 0.3 (1.8) 0.13 (0.7) 1.9 (7.5) 0.8 (4.5) Sarawak 0 (0-13) 0 (0-5) 0 (0-43) 0 (0-43)
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Table 3: Average time between order and delivery of medicines in 20 remote public health facilities Average time between order and delivery, number of days
mean (SD), median (range) 2014 2015 2016 Average State 7.0 (4.4) 8.8 (2.7) 5.7 (2.1) 7.3 (11.9) Selangor 7.0 (2-20) 8.0 (6-15) 6.0 (2-10) 7.0 (2-20) 8.7 (5.7) 8.6 (4.9) 9.6 (7.4) 9.0 (6.1) Pahang 6.0 (2-22) 7.0 (3.22) 7.0 (1-32) 6.0 (1-32) 11.2 (7.2) 10.8 (8.6) 8.5 (7.4) 10.1 (7.8) Johor 11.0 (2-26) 7.0 (2-34) 4.0 (1-24) 7.0 (1-34) 17.0 (11.7) 15.3 (10.1) 13.5 (8.6) 15.3 (10.2) Sarawak 14.0 (2-64) 13.0 (2-54) 11.0 (1-37) 13.0 (1-64)
Discussion According to the WHO, access to medicines can be addressed in relation to the physical availability of essential medicines and stockout duration, and affordability and prices of medicines. Apart from that, it can also be discussed using data on access to health facilities8. In this report, availability of essential medicines, stockout duration and time between order and delivery of medicines were discussed. The findings showed that the availability of essential medicines on the day of survey remained high with more than 96% of medicines were kept in the remote public health facilities. These findings were consistent with a study by Kamaruzaman et al. in 2005 that was conducted in 20 randomly selected public health facilities in Malaysia. It was reported that the availability of essential medicines in public health facilities was 95.4%5. Alternatives are available even though some of the medicines were not available or out of stock. For example, tablet simvastatin 40mg was available to substitute for simvastatin 20mg which was not available in some remote public health facilities. Purchasing tablet simvastatin 40mg was a good option because it made the medicine readily available for patients requiring simvastatin 20 mg by halving the 40mg dose and it also reduces the total amount spent on simvastatin. Referring to the Consumer Price Guide by the Pharmaceutical Services Division Malaysia, the price for a tablet of Simvastatin 40mg which can make up for two doses of simvastatin 20mg is cheaper compared to a single dose of simvastatin 20mg9. In an efficient distribution system, the time between order and delivery should be approximately the same for each order and as short as possible depending on the distance and the number of intermediate levels10. Sarawak had the longest time between ordering and delivery of medicines as compared to other states. Most of the medicine distribution centres or suppliers are based in Peninsular Malaysia. From Peninsular Malaysia to Sabah and Sarawak, medicines are 12 transported by air or water transport, which might explain the delay of the delivery time to the public district drug stores in these areas. The transportation system is not as established as in Peninsular Malaysia and this could also be a contributing factor to a more extended delivery time to the remote public health facilities5. Inevitable setbacks such as weather, tide and water levels might affect shipment of medicines logistically. Therefore, supplying to remote health facilities becomes a challenge. Stock out is the period where the medicine is out of stock in the store of the remote public health facility. Comparing the stock out duration of essential medicines in remote public health facilities, three states were found to have an average median of zero-day stock out, except Johor. Despite these, the maximum stock out day indicated a stock management challenge for all states. In a verbal conversation with pharmacists in the public health facilities in Selangor and Pahang, the stock 12 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 outs of some essential medicines were mainly due to financial constraints which usually happened at the end of the year, thus delaying procurement and supply from the suppliers. However, the real causes of stock outs require further investigation. During the stock out periods, patients still received their supplies through remaining medicine stocks at the dispensing counters, and stocks received or on loan from other health facilities. On the other hand, even though drug distribution in Sarawak covers a wide area, it had an average stock out of less than one day. This could be attributed to the effectiveness of public district drug stores in organising the distribution of stocks to the health facilities. Also, the adherence to proper scheduling of drug stock management is also important since these public remote health facilities are located miles away from the district drug store. There are a few limitations in our study. Due to limited resources and logistical constraints, northern zone was not included in the study. In addition, the high turnover rate of data collectors in the remote health facilities was observed and this might have contributed to inconsistency in data collection. Nevertheless, frequent verbal clarification was conducted to minimise the inconsistency.
Conclusion The availability of essential medicines at selected remote public health facilities in Malaysia was high with the availability of more than 95%. This is in line with the WHO’s recommendation of 80% of essential medicines availability to ensure equitable access and the rational use of medicines. The overall performance of distribution system and efficacy of drug stock management in remote health facilities can be improved to ensure that medicines are efficiently distributed throughout the country and patients have access to continuous supply of medication.
Acknowledgement We would like to thank the Director General of Health Malaysia for his permission to publish this article. The authors would also like to acknowledge Dr. Hasenah binti Ali and Madam Nur’Ain Shuhaila binti Shohaimi from the Pharmacy Policy and Strategic Planning Division and Mr. Fahmi bin Hassan from the Pharmacy Practice and Development Division for their opinions and contributions in this research.
Conflict of Interest Statement No external funding was received and the authors declared no conflict of interest.
References
1. Essential Medicines. World Health Organization 2017. Available from: http://www.who.int/topics/essential_medicines/en/ 2. WHO Medicines Strategy 2004–2007. Geneva: World Health Organization. 2004. Available from: 13 http://apps.who.int/medicinedocs/en/d/Js5416e/ 3. IMS Institute for Healthcare Informatics. Understanding the Role and Use of Essential Medicines Lists April 2015. 4. Malaysia National Medicines Policy 2nd Edition, Ministry of Health Malaysia. 5. Kamaruzaman S, Mohamed I. M. Ibrahim. Are Essential Medicines in Malaysia Accessible, Affordable and Available? Pharmacy World and Science. December 2005, Volume 27, Issue 6, pp 442–446. 6. Bazargani, Y.T., Ewen, M., de Boer, A., Leufkens, H.G. and Mantel-Teeuwisse, A.K., Essential medicines are more available than other medicines around the globe. PLoS One, 2014. 9(2), p.e87576.
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7. Loius N. et al. Assessment of essential medicines stock-outs at health centers in Burera District in Northern Rwanda. Rwanda journal Series F: Medicine and Health Sciences Vol 2 No 1, 2015. 8. WHO Operational package for assessing, monitoring and evaluating country pharmaceutical situations. Guide for coordinators and data collectors. World Health Organization. 2007. http://apps.who.int/medicinedocs/documents/s14877e/s14877e.pdf 9. Brudon, P.; Rainhorn, J.; Reich, M.R. Indicators for monitoring national drug policies. A practical manual second edition. World Health Organization. 1999. http://apps.who.int/medicinedocs/pdf/whozip14e/whozip14e.pdf 10. Consumer Price Guide. Pharmaceutical Services Programme, Ministry of Health Malaysia. Available from: https://www.pharmacy.gov.my/v2/en/apps/drug-price 11. Yang, H.; Dib, H.H.; Zhu, M.; Qi, G.; Zhang, X. Prices, availability and affordability of essential medicines in rural areas of Hubei Province, China. Health Policy and Planning. 2009, 25(3), 219- 229.
Appendix 1
LIST OF SELECTED REMOTE PUBLIC HEALTH FACILITIES
Selangor Johor Tanjung Karang Health Clinic Mersing Kanan Health Clinic Sungai Besar Health Clinic Endau Health Clinic Sekinchan Health Clinic Labis Health Clinic Bekok Health Clinic Pahang Damak Health Clinic Sarawak Bukit Betong Health Clinic Bintangor Health Clinic Pekan Awah Health Clinic Song Health Clinic BandarTun Razak Health Clinic Lawas Health Clinic Bandar Jengka Health Clinic Batu Niah Health Clinic Cheroh Health Clinic Kanowit Hospital Selangau Health Clinic Sri Aman Health Clinic
Appendix 2
BASKET OF DRUGS
14 Tablet Amlodipine 5mg Tablet Metoprolol 100mg Tablet Gliclazide 80mg Tablet Chlorpheniramine 4mg Tablet Perindopril 4mg Tablet Acetylsalicylic acid 300mg Tablet Metformin 500mg Tablet Frusemide 40mg Tablet Hydrochlorothiazide 25mg Tablet Simvastatin 20mg
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Adverse Drug Reactions of Clozapine and Their Management in a Tertiary Care
Hospital in Kelantan
Nazmi Liana Azmi1, Fazlina Mohamed1, Nurul Khairiyah Wanik1, Chua Siew May1, Nur ‘Izzati Ahmad Zawawi1
1 Hospital Raja Perempuan Zainab II, Ministry of Health Malaysia
Abstract
Introduction: Clozapine remains as the most effective antipsychotic for the treatment of resistant schizophrenia. However, it has a wide range of adverse drug reactions (ADRs) which may cause significant distress and affects treatment outcome. Objective: We aimed to identify ADRs associated with clozapine and their management among patients at outpatient psychiatric clinic in Hospital Raja Perempuan Zainab II, Kelantan. Methods: A secondary data review was conducted from November 2016 to April 2017. The inclusion criteria were all adult patients on long term clozapine treatment with at least 3 regular follow-ups. Patients with incomplete medical records were excluded from the study. Results: A total of 50 patients were involved with 199 ADRs recorded. Subjects were mostly male (70%, n=35), Malays (84%, n=42) with mean age of 38.7 (SD 9.4) years old. The mean duration of treatment with clozapine was 61.1 (SD 29.9) months. It was noted that majority of the patients developed weight gain (66%, n=33) as there was a statistically significant difference between baseline and current body mass index (p=0.015). Other common ADRs were sedation (52%, n=26), followed by upper respiratory tract infection (48%, n=24), constipation (36%, n=18) and hypersalivation (34%, n=17). No incidence of agranulocytosis or thrombocytopenia was observed in our study. This was consistent with the laboratory findings since no statistically significant differences were noted between baseline and current total white blood cells as well as platelet count (p=0.770 and p=0.201, respectively). Conclusion: Our study added to the existing information on the patterns of ADRs following clozapine treatment at a local facility. Fortunately, all ADRs reported were tolerable and manageable. Nevertheless, a careful increase in clozapine dosage and regular laboratory monitoring are strict requirements.
Keywords: clozapine, adverse drug reactions, antipsychotics, schizophrenia
NMRR ID: NMRR-16-2654-33392 15
Corresponding author: Nazmi Liana Azmi Department of Pharmacy, Hospital Raja Perempuan Zainab II, 15586 Kota Bharu, Kelantan Email: [email protected]
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Introduction Schizophrenia is one of the most complex and debilitating mental illnesses. It interferes with one’s ability to think clearly, manage emotions, make decisions and relate to others. It represents a heterogeneous syndrome of hallucinations, delusions, negative symptoms and cognitive issues. Antipsychotics have been the mainstay of therapy and amongst them is clozapine1. Clozapine has existed for more than half a century since it was first synthesised in 19562. Early clinical trials had confirmed its efficacy which led to the introduction of clozapine into clinical practice in Europe in the 1970s. Clozapine was, however, withdrawn from the market after fatal cases of agranulocytosis were reported in Finnish patients. It was then reintroduced in 1990 after the results of a major clinical trial were published in favour of clozapine3. Other studies later also demonstrated that clozapine was proven to be superior to other antipsychotics for treatment-resistant schizophrenia4,5. Treatment- resistant schizophrenia occurs in approximately 30% of patients with schizophrenia. There are various definitions; but usually patients are diagnosed with treatment-resistant schizophrenia when they have at least moderate impairment in functioning as a result of failure to respond to any two antipsychotics administered at adequate dosage and duration. At this point, they may benefit from clozapine which is the only antipsychotic indicated for treatment-resistant schizophrenia6,7. In spite of its reputation as the most effective antipsychotic, clozapine has many adverse drug reactions (ADRs) which may limit its use8. Prescribers are usually hesitant to start their patients with clozapine for fear of the ADRs2,8–10. These ADRs ranges from annoying to noxious and potentially harmful2. They can occur in many organ systems with the most affected are central nervous system (sedation, dizziness, headache and tremor), cardiovascular system (tachycardia, hypotension and syncope), autonomic nervous system (hypersalivation, weight gain, sweating, dry mouth and visual disturbances) and gastrointestinal system (constipation and nausea)10. In the long run, patients can develop metabolic syndrome and type 2 diabetes mellitus. It also predisposes patients to rare but life- threatening events of agranulocytosis, cardiomyopathy and myocarditis11–13. Apart from that, there are cases of adverse cutaneous drug reactions (ACDRs) reported among patients commencing clozapine10. These ADRs generally take place during the initial stage of therapy which can prompt patients to withdraw from the treatment14. Often the main reason for discontinuation of clozapine is its intolerable ADRs. In a retrospective cohort study, it was found that 45% of patients discontinued their first trial of clozapine within 24 months of therapy. It was observed that the risk of treatment withdrawals due to ADRs was highest in the first few months of clozapine initiation8. Therefore, it is important to maintain the appropriate management of ADRs to ensure that treatment outcome is not affected. Dosage adjustment can greatly help in minimising the occurrence of ADRs15. Patients who experienced frequent but non severe ADRs of increased appetite, sedation, enuresis and hypersalivation usually do not require reduced doses or drug intervention14. Nevertheless, it is always recommended that regular assessment and blood monitoring should be done prior to and after initiation of clozapine to prevent complications and fatal incidences of ADRs2,4,12. 16 There is an abundance of literature published in the 80’s and 90’s but little is documented on the local practice of clozapine. Therefore, we aimed to identify ADRs associated with clozapine and their management among psychiatric patients in a tertiary care hospital in Kelantan. It was hoped that the findings can shed some light on the current clinical experience with this drug as compare to other practices.
Methods A secondary data review was conducted for a duration of 6 months which was from November 2016 to April 2017 at the outpatient psychiatric clinic in Hospital Raja Perempuan Zainab II, Kelantan. The inclusion criteria were all adult patients on long term clozapine treatment with at least three regular visits. Patients with incomplete medical records were excluded. The list of the patients prescribed with 16 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 clozapine was obtained from outpatient psychiatric clinic. Data collection form was used to collect demographic characteristics of patients, types and frequencies of ADRs as well as their management from all available medical records at the time. Data was entered and analysed using IBM SPSS Statistics version 20.0. All categorical data in the demographic characteristics were presented as frequencies (n) and percentages (%) while continuous variables were expressed as mean and standard deviation (SD). Descriptive statistics were also used to explain ADRs associated with clozapine and their management among psychiatric patients. Paired t-test was applied to check the differences between baseline and current body mass index, total white blood cells and platelet count. A p-value of <0.05 was considered as statistically significant. This research was submitted to Medical Research and Ethical Committee (MREC) for ethical approval and was granted with National Medical Research Registry (NMRR) identity number of NMRR-16-2654-33392. Permission to conduct the study at the site was obtained from the Director of Hospital Raja Perempuan Zainab II. The research was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Subject’s confidentiality was protected with no reference to a specific individual.
Results A total of 102 medical records were reviewed. After exclusion, only 50 subjects were included in the study. Patients were mostly male (70%), Malays (84%) with mean age of 38.7 (SD 9.4) years old. Many of them were prescribed with initial and maintenance clozapine dose of between 100 to 200mg daily. The mean duration of clozapine treatment was 61.1 (SD 29.9) months (Table 1). A total of 199 ADRs was recorded. A majority of patients developed weight gain (66%, n=33) and the difference between baseline and current body mass index was statistically significant (p<0.05). Other common ADRs were sedation (52%, n=26), upper respiratory tract infection (48%, n=24), constipation (36%, n=18) and hypersalivation (34%, n=17). Skin reaction (32%, n=16), headache (30%, n=15) and palpitation (26%, n=13) were also prevalent among our study population. Some even complained of having rigidity (18%, n=9), blurred vision (12%, n=6) and restlessness (10%, n=5) during the course of clozapine treatment. Only a minority reported ADRs of hyperglycaemia (4%, n=2), cardiovascular effect (4%, n=2) and seizure (4%, n=2) (Table 2). No incidence of agranulocytosis or thrombocytopenia was observed. This was consistent with the laboratory findings since no statistically significant differences were noted between baseline and current values for total white blood cells and platelet count (p=0.770 and p=0.201, respectively) (Table 3). Symptomatic treatments were given for ADRs of upper respiratory tract infection, constipation, skin reaction and epigastric pain. These ADRs were adequately managed with over-the-counter drugs. Antipyretic, antihistamine, mucolytic agent and cough syrup were prescribed for upper respiratory tract infection. Laxatives were given for constipation while antifungal and topical corticosteroids were 17 endorsed for skin reaction. As for epigastric pain, it was treated with antacid and oral histamine-2 blocker. All ADRs were either mild or moderate and were successfully intervened without dosage adjustment (Table 4).
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Table 1: Demographic characteristics of study population (N=50)
Characteristics n (%) / mean (SD) Age, year, mean (SD) 38.7 (9.4) Gender, n (%) Male 35 (70) Female 15 (30) Ethnicity, n (%) Malay 42 (84) Others 8 (16) Initial clozapine dose, n (%) 100 – 200 mg 36 (72) > 200 – 300 mg 9 (18) > 300 mg 5 (10) Current clozapine dose, n (%) 100 – 200 mg 25 (50) > 200 – 300 mg 13 (26) > 300 mg 12 (24) Duration of clozapine treatment, month, mean (SD) 61.1 (29.9)
Table 2: ADRs of clozapine among study population (N=199) ADR n (%) Weight gain 33 (66) Sedation 26 (52) Upper respiratory tract infection 24 (48) Constipation 18 (36) Hypersalivation 17 (34) Skin reaction 16 (32) Headache 15 (30) Palpitation 13 (26) Epigastric pain 11 (22) Rigidity 9 (18) Blurred vision 6 (12) Restlessness 5 (10) Hyperglycaemia 2 (4) Cardiovascular effect 2 (4) Seizure 2 (4) 18
Table 3: Comparison of baseline and current laboratory parameters Baseline, Current, Laboratory parameter Indication p-value* mean (SD) mean (SD) Body mass index, kg/m2 Weight gain 25.0 (5.6) 28.4 (14.0) 0.015 White blood cell, x10/L Agranulocytosis 8.7 (2.1) 8.7 (2.1) 0.770 Platelet, x10/L Thrombocytopenia 273.3 (64.4) 278.7 (66.2) 0.201 * Paired t-test, normality assumed
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Table 4: Pharmacological management of ADRs among study population ADR Management
Paracetamol tablet Chlorpheniramine tablet Upper respiratory tract infection Bromhexine tablet Diphenhydramine syrup Lactulose syrup Constipation Glycerine enema Miconazole cream Skin reaction Betamethasone cream Mixture magnesium trisilicate Epigastric pain Ranitidine tablet
Discussion Clozapine continues to be the gold standard and cornerstone therapy for treatment-resistant schizophrenia. It has been proven to successfully treat symptoms and improve the condition of these patients. Evidence also clearly showed that clozapine has the advantage of reducing the risk of mortality and aggression over other available antipsychotics3. Despite its effectiveness, it causes the worst metabolic disturbances among antipsychotics. Like many other reports, we found that clozapine was strongly associated with weight gain16. An increase of at least 7% of baseline weight gain was considered as clinically significant, which was in agreement with our study population17. It was said that this ADR is time-related, whereby weight and body mass index increase significantly over time. There were patients who put on up to 9.2 kg18 and 13.5 kg17 during the course of their treatment. In order to overcome this problem, Siskind and colleagues suggested that prescribing metformin could promote weight loss for people with obesity on clozapine16. There are many other common ADRs associated with clozapine. Most of our patients complained of a high rate of sedation and headache upon taking clozapine. Both were frequent but troubling adverse events involving the central nervous system2,3,10. Sedation seems to be multifactorial19 and can be associated with the fact that clozapine is a strong histamine H1 receptor antagonist20. The management is still unclear but reducing the dose of clozapine may alleviate the effect19. Prescribers should discuss and negotiate the dosing schedule with patients. Treatment augmentation with drugs such as aripiprazole may help to reduce the required clozapine dose and thus decrease sedation, but should not be prescribed without the consultation of a psychiatrist7. Other than that, clozapine also affects the autonomic nervous system which causes hypersalivation (sialorrhea) and visual disturbances10. We found that one third of our patients experienced drooling which was consistent with previous systematic review21. However, this figure 19 was far lower than Maher et al.’s study in 2016 who reported that over 90% of their study population suffered from hypersalivation22. This ADR can be troublesome as it interrupts sleep which eventually influences quality of life21,22. Hypersalivation, particularly while sleeping can be embarrassing and stigmatising to the patients. Sublingual anticholinergic drugs may have some effect on the ADR7. As for visual disturbances, clozapine has been listed as one of the drugs that can cause difficulty with focusing at near and blurred vision23. This could explain why some of our study population complained of blurred vision. If left untreated, it may lead to worsening eye problems which may cause permanent damage to the sight24. Patients who are prescribed with clozapine are prone to fever, cold and flu-like symptoms due to viral upper respiratory tract infections. In most situations, patients do not require adjustment of therapy. This might be the reason our prescribers resorted to over-the-counter medications such as
19 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 paracetamol and antihistamines for symptomatic relief. However, it is wise not to ignore these signs and symptoms as they may indicate something far serious, for instance myocarditis or secondary infections due to neutropenia. Full blood count must be checked so that these conditions can be ruled out7. Clozapine also increases the risk of pneumonia, although its relationship is said to be complex. Ironically, among possible indirect mechanisms that predispose clozapine-treated patients to infection is the ADR of hypersalivation itself 25. Gastrointestinal reactions are prevalent with clozapine which explain the rationale behind our findings. It can affect the whole gastrointestinal system and has varying degrees of impairment. The incidence of constipation was reported between 22% and 33%, and up to 60% of patients with clozapine10. This problem causes patients to be highly dependent on laxatives26, as seen in our patients. In worst circumstances, there has been reports of deaths due to severe gastrointestinal hypomotility10,13. Preventative actions need to be taken at the first sign of constipation. Patients should be encouraged to maintain consistent intake of sugar-free fluid and practise regular exercise7. It is suggested that prescribers should use the lowest effective dose of clozapine and avoid concomitant drugs that have effect on bowel motility26, such as drugs with significant anticholinergic effects like oxybutin and amitriptyline 7. Our least reported ADRs were hyperglycaemia, cardiovascular effect and seizure. Hyperglycaemia is considered as a rare metabolic ADR10 but the incidence is closely related to weight gain as well as clozapine-induced insulin resistance2,27. Paradoxically, cardiovascular events such as tachycardia are not uncommon in patients prescribed with clozapine. A fast pulse rate often leads to palpitations which can be treated with beta-blockers and calcium-channel blockers28. The risk of developing myocarditis or cardiomyopathy as severe cardiac problems, however, is very low (0.015% to 0.188%)2,10,13. Although seizure and rigidity are considered as common ADRs10,13, our results corresponded to the work by Maher et al. (2016), whereby only a small number of cases were recorded. Clozapine has been associated with seizures with a cumulative one-year risk of approximately 3 to 5%. These seizures include a wide variety of epileptic activity and not just generalised tonic-clonic seizures. Patients who have seizures while taking clozapine must be referred to emergency department immediately. Clozapine concentrations, testing for illicit drugs, brain imaging and neurology review may be required. An accurate diagnosis of seizures is essential before the decision to stop clozapine is made. Prescribers may consider adding antiepileptic drug such as sodium valproate or lamotrigine to the patient’s regime. Nevertheless, it is important to consult the psychiatrist before commencing any changes to a patient’s standard care7,11. On the other hand, rigidity or muscular stiffness should not be taken lightly at any time. It may indicate a bigger concern if accompanied by other symptoms like hyperthermia and instability of cardiorespiratory parameters, which are the symptoms of neuroleptic malignant syndrome. It is an uncommon and lethal neurological disorder, attributed to the administration of antipsychotics, for example clozapine29. Other observed ADRs were epigastric pain (gastrointestinal upset), restlessness (agitation) 20 and skin reactions22. Gastrointestinal problem is a common and dose-related ADR of clozapine. They can be treated with proton pump inhibitors and in our setting, antacid and histamine-2 blocker were used. Although there were reports of omeprazole affecting clozapine concentrations, all proton pump inhibitors are generally considered to be safe to use in patients taking clozapine7. Agitation is often exhibited as ADR in patients treated with antipsychotic. However, only a few cases were associated with clozapine22,30. Interestingly, we observed a high number of ACDRs in our study population. For these ADRs, antifungal and steroid cream were prescribed. This was worth noting as skin reaction is always regarded as an uncommon ADR in patients with clozapine. Minor ACDRs had occurred in 2% to 5% of patients, with only a few reports on severe skin reactions10,31. None of our study population experienced any serious ADR during the course of their treatment. Most cases were adequately managed by symptomatic treatments. This may be due to the 20 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 fact that physical health assessment and blood monitoring are mandatory requirements in our setting. Our study revealed that the management were only for upper respiratory tract infection, constipation, skin reaction and epigastric pain. A structured approach to clozapine monitoring is vital to prevent the risk of rare but deadly ADRs such as agranulocytosis7,13. Even though it was postulated that its incidence decreases over time of clozapine treatment, cases of late-onset of agranulocytosis have been witnessed32. Routine assessment is a must at baseline and should be made compulsory to be repeated at constant intervals. Full blood count, urea and electrolytes as well as liver function test are required at the start of clozapine treatment and once per year. It is recommended that physical health monitoring which includes cardiovascular risk assessment to be done on patients diagnosed with schizophrenia annually. Weight, body mass index and waist circumference should be checked at baseline, 1 month, 3-monthly and then yearly. Blood pressure monitoring is advised before starting therapy and frequently during dose titration of clozapine. Also, patients with medical history of cardiovascular disease should be subjected to regular electrocardiogram. Other than that, fasting blood glucose needs to be measured at baseline, 1 month and then 4 to 6-monthly. As for lipid profile, it is advised that it is checked at baseline, 3-monthly in the first year and then annually. Electroencephalogram is not essential but may be indicated for patients with pre-existing compromised brain function or seizures. In addition to the investigations and specific assessments for clozapine, there is an urge for usual monitoring relevant for any other medications concurrently prescribed for the patient. Monitoring for ADRs must be done regularly during each follow up7,9,13. Our study had several limitations. Due to the nature of retrospective design, we may miss out some of the important clinical characteristics and were unable to pinpoint all management for ADRs. We were unable to determine causal relationship and factors associated with ADRs in clozapine- treated patients. Furthermore, some assumptions were made when the description of ADRs were written vaguely. These issues can be resolved by utilising research with prospective study design. Another way is by opting for qualitative approach to provide in-depth details on the subject matter. The small sample size also limited us from generalising the findings to the entire population. Therefore, caution should be exercised when interpreting the results. A multicentre study involving more facilities from other regions in Malaysia which incorporates probability sampling method is recommended to avoid potential bias. Notwithstanding these limitations, the results are still worthy of further research.
Conclusion Our study adds to the existing information on the pattern of ADRs following clozapine treatment at a local facility. Fortunately, all ADRs reported were tolerable and manageable. It is important to bear in mind that appropriate management of ADRs can facilitate maximum outcome of clozapine treatment. Physicians and patients alike should be aware that the benefit of clozapine use is wider than its risk. Nevertheless, a careful increase in clozapine dosage and regular laboratory monitoring are strict requirements. 21
Acknowledgement This study was supported by the Department of Psychiatry, Hospital Raja Perempuan Zainab II, Kelantan. We would like to thank the Director General of Health Malaysia for his permission to publish this article. We also wish to extend our heartfelt gratitude to those who have helped us along the way.
Conflict of Interest Statement No external funding was received and the authors declared no conflict of interest.
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References 1. Jain, T.; Bhandari, A.; Ram, V.; Parakh, M.; Wal, P.; Nagappa, A. N. Drug Interactions and Adverse Drug Reactions in Hospitalized Psychiatric Patients A Critical Element in Providing Safe Medication Use. Ger. J. Psychiatry. 2011, 14, 26-34. 2. Meltzer, H. Y. Clozapine: Balancing Safety with Superior Antipsychotic Efficacy. Clinical Schizophrenia and Related Psychoses. 2012. 3. Warnez, S.; Alessi-Severini, S. Clozapine: A Review of Clinical Practice Guidelines and Prescribing Trends. BMC Psychiatry 2014, 14, 102. 4. Essali, A.; Al-Haj Haasan, N.; Li, C.; Rathbone, J. Clozapine versus Typical Neuroleptic Medication for Schizophrenia. Cochrane Database Syst. Rev. 2009, No. 1. 5. Agid, O.; Foussias, G.; Singh, S.; Remington, G. Where to Position Clozapine: Re-Examining the Evidence. Can. J. Psychiatry 2010, 55 (10), 677–684. 6. Lally, J.; Gaughran, F.; Timms, P.; Curran, S. R. Treatment-Resistant Schizophrenia : Current Insights on the Pharmacogenomics of Antipsychotics. 2016, 117–129. 7. Winckel, K.; Siskind, D. Clozapine in Primary Care. Aust. Prescr. 2017, 40 (6), 231–236. 8. Legge, S. E.; Hamshere, M.; Hayes, R. D.; Downs, J.; O’Donovan, M. C.; Owen, M. J.; Walters, J. T. R.; MacCabe, J. H. Reasons for Discontinuing Clozapine: A Cohort Study of Patients Commencing Treatment. Schizophr. Res. 2016, 174 (1–3), 113–119. 9. Tungaraza, T. E.; Farooq, S. Clozapine Prescribing in the UK: Views and Experience of Consultant Psychiatrists. Ther. Adv. Psychopharmacol. 2015, 5 (2), 88–96. 10. De Fazio, P.; Gaetano, R.; Caroleo, M.; Cerminara, G.; Maida, F.; Bruno, A.; Muscatello, M. R.; Moreno, M. J. J.; Russo, E.; Segura-García, C. Rare and Very Rare Adverse Effects of Clozapine. Neuropsychiatr. Dis. Treat. 2015, 11, 1995–2003. 11. Raja, M.; Raja, S. Clozapine Safety, 40 Years Later. Curr. Drug Saf. 2014, 9 (3), 163–195. 12. Merrill, D. B.; Dec, G. W.; Goff, D. C. Adverse Cardiac Effects Associated with Clozapine. J. Clin. Psychopharmacol. 2005, 25 (1), 32–41. 13. Kar, N.; Barreto, S.; Chandavarkar, R. Clozapine Monitoring in Clinical Practice: Beyond the Mandatory Requirement. Clin. Psychopharmacol. Neurosci. 2016, 14 (4), 323–329. 14. Aronson, J. K.; Meyler, L. Meyler’s Side Effects of Drugs : The International Encyclopedia of Adverse Drug Reactions and Interactions; 2016. 15. Lieberman, J. A. Maximizing Clozapine Therapy: Managing Side Effects. J. Clin. Psychiatry 1998, 59 Suppl 3, 38–43. 16. Siskind, D. J.; Leung, J.; Russell, A. W.; Wysoczanski, D.; Kisely, S. Metformin for Clozapine Associated Obesity: A Systematic Review and Meta-Analysis. PLoS One 2016, 11 (6), 1–15. 17. Volpato, A. M.; Zugno, A. I.; Quevedo, J. Recent Evidence and Potential Mechanisms Underlying Weight Gain and Insulin Resistance Due to Atypical Antipsychotics. Rev. Bras. Psiquiatr. 2013, 35 (3), 295–304. 18. Henderson, D. C.; Nguyen, D. D.; Copeland, P. M.; Hayden, D. L.; Borba, C. P.; Louie, P. M.; 22 Freudenreich, O.; Evins, A. E.; Cather, C.; Goff, D. C. Clozapine, Diabetes Mellitus, Hyperlipidemia, and Cardiovascular Risks and Mortality: Results of a 10-Year Naturalistic Study. J. Clin. Psychiatry 2005, 66 (9), 1116–1121. 19. Perdigués, S. R.; Quecuti, R. S.; Mané, A.; Mann, L.; Mundell, C.; Fernandez-Egea, E. An Observational Study of Clozapine Induced Sedation and Its Pharmacological Management. Eur. Neuropsychopharmacol. 2016, 26 (1), 156–161. 20. Shirazi, A.; Stubbs, B.; Gomez, L.; Moore, S.; Gaughran, F.; Flanagan, R.; MacCabe, J.; Lally, J. Prevalence and Predictors of Clozapine-Associated Constipation: A Systematic Review and Meta- Analysis. Int. J. Mol. Sci. 2016, 17 (6), 863. 21. Syed, R.; Au, K.; Cahill, C.; Duggan, L.; He, Y.; Udu, V.; Street, C. Europe PMC Funders Group Pharmacological Interventions for Clozapine-Induced Hypersalivation. 2014, No. 3. 22 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018
22. Maher, S.; Cunningham, A.; O’Callaghan, N.; Byrne, F.; Mc Donald, C.; McInerney, S.; Hallahan, B. Clozapine-Induced Hypersalivation: An Estimate of Prevalence, Severity and Impact on Quality of Life. Ther. Adv. Psychopharmacol. 2016, 6 (3), 178–184. 23. Smith, J. L.; Buncic, J. R. Drugs Which Can Affect Near Vision: A Useful List. Drugs 2000, No. C. 24. Sönmez, İ.; Aykan, Ü. Psychotropic Drugs and Ocular Side Effects. Türk Oftalmol. Derg. 2013, 43 (4), 270–277. 25. Van Os, J. A Salience Dysregulation Syndrome. Br. J. Psychiatry 2009, 194 (2), 101–103. 26. Every-Palmer, S.; Nowitz, M.; Stanley, J.; Grant, E.; Huthwaite, M.; Dunn, H.; Ellis, P. M. Clozapine - Treated Patients Have Marked Gastrointestinal Hypomotility , the Probable Basis of Life - Threatening Gastrointestinal Complications : A Cross Sectional Study. 2016. 27. Lund, B. C.; Perry, P. J.; Brooks, J. M.; Arndt, S. Clozapine Use in Patients with Schizophrenia and the Risk of Diabetes, Hyperlipidemia, and Hypertension: A Claims-Based Approach. Arch. Gen. Psychiatry 2001, 58 (12), 1172–1176. 28. Lally, J.; Mj, D.; Jh, M. Pharmacological Interventions for Clozapine-Induced Sinus Tachycardia ( Review ) SUMMARY OF FINDINGS FOR THE MAIN COMPARISON. 2016, No. 6, 2–4. 29. Leonardo, Q.-F.; Juliana, G.-R.; Fernando, C.-A. J. Atypical Neuroleptic Malignant Syndrome Associated with Use of Clozapine. Case Rep. Emerg. Med. 2017, 2017, 2174379. 30. Shaikh, F.; professor, A. Issue: 3; March 2016 International Journal of Health Sciences and Research Conclusion: Maximum Number of ADRs Observed with Olanzapine 28(14.21%) Followed by Risperidone 23(11.67%). 6, 162. 31. Goldstein, S., Wintroub, B. Adverse Cutaneous Reactions to Medication. 1996, 18 (1), 56–67. 32. Singh, A.; Grover, S.; Malhotra, P.; Varma, S. C. Late Onset Agranulocytosis with Clozapine Associated with HLA DR4 Responding to Treatment with Granulocyte Colony-Stimulating Factor: A Case Report and Review of Literature. Clin. Psychopharmacol. Neurosci. 2016, 14 (2), 212– 217.
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A Prospective Study on Antibiotic De-escalation Practice in the Medical Wards of
Penang General Hospital
Wong Kar Loon1, Wong Mei Ling1, Chong Zan Kai1, Siva Malar Ganasen1, Wan Sakinah Wan Hasbullah1, Chee Sze Hui1, Chow Ting Soo2, Leong Kar Nim2, Wong Peng Shyan2, Ch’ng Wei Choong3
1 Department of Pharmacy, Hospital Pulau Pinang, Ministry of Health Malaysia 2 Infectious Disease Unit, Hospital Pulau Pinang, Ministry of Health Malaysia 3 Pathology Department, Hospital Pulau Pinang, Ministry of Health Malaysia
Abstract
Introduction: The increase of antimicrobial resistance (AMR) rate is a burden to the country due to the high treatment cost and increased mortality rate. One of the strategies to reduce AMR under antimicrobial stewardship (AMS) was antibiotic de-escalation. Objective: The objective of the study was to assess the practice of antibiotic de-escalation and the reasons of not de-escalating antibiotics therapy in the medical wards of Penang General Hospital. Methods: This prospective study was carried out in three medical wards of Penang General Hospital for three months. The frequency of de-escalation and the reasons for no de-escalation were determined. Results: Among 99 patients included in this study, antibiotics were de-escalated in 86 patients (86.9%). The most stated reasons for no de-escalation were clinical deterioration (28%), fear of de- escalation in complicated patients (20%), and immuno-compromised patients (12%). There was no significant difference in the length of hospitalisation between the de-escalation and no de-escalation group. Conclusion: The percentage of antibiotic de-escalation in medical wards of Penang General Hospital was high. Thus, this study may serve as a precedent to introduce AMS with antibiotic de-escalation to other disciplines or wards to help tackle the increasing AMR rate.
Keywords: quality use of medicines, Penang, antibiotic, de-escalation, antimicrobial stewardship
NMRR ID: NMRR-17-857-35440
Corresponding author:
Wong Kar Loon 24 Pharmacy Department, Hospital Pulau Pinang, Jalan Residensi, 10990 Georgetown, Pulau Pinang. Email: [email protected]
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Introduction Antimicrobial resistance (AMR) have been steadily increasing worldwide, which causes increase in cost of treatment and mortality rate1,2. This AMR crisis have been reported to occur due to antibiotics overuse and misuse such as inappropriate antibiotics prescribing practice for colds which viruses are the most common causative agent, thus causing redundancy in antibiotic prescribed3. In addition, the lack of new antibiotics development, extensive agricultural use of antibiotics and regulatory barriers associated with drug use and development are also the contributing factors to the rising AMR worldwide4. The resistance rate in Malaysia was reported to increase among the regularly used antibiotics against common local bacteria such as Staphylococcus aureus, Streptococcus pneumonia, Klebsiella pneumonia and Escherichia coli based on data obtained from the hospitals in the country5. The National Antibiotic Guideline and Antimicrobial Stewardship (AMS) Programme were implemented to reduce AMR6,7. Antibiotics de-escalation, which is a component of AMS, has been implemented to cope with current emergence of AMR7. Antibiotic de-escalation involves three vital components, which are switching from broad spectrum to a narrow spectrum antibiotic, stopping the on-going antimicrobial treatment once no infection is identified, and / or use a single antibiotic instead of multiple agents based on clinical response, culture results and susceptibilities of the microorganism identified8. Morel et al. reported that recurrent infection was found to be lower (5%) in patient with de-escalation compared to patient without de-escalation (19%, p=0.01)9. In addition, Singh et al. also stated AMR were only documented in 15% of the patients in the de-escalation group compared to 35% in patients receiving standard antibiotic therapy (p=0.017)10. Besides that, decrease in the length of stay was also found to be associated with de-escalation practice11,12. Although the importance and safety of de-escalation have been well documented, the rate of antibiotic de-escalation was still reported to be inadequate. Antibiotic de-escalation was only accomplished in approximately 35–50% of the patients with severe sepsis and this was considered unsatisfactory9,13,14. In addition, a study showed that antibiotic de-escalation was only performed in 28.3% of 9,319 patients admitted with healthcare-associated pneumonia15. Salahuddin reported that de-escalation failure was commonly observed in critically ill patients, as antimicrobial de-escalation only occurred in 48% of patients. This reflected the physicians’ reluctance to de-escalate antibiotic therapy in complicated and sicker patients, or in multidrug resistance or fungal sepsis16. Several reasons could explain these unsatisfying rates of antibiotic de-escalation by physicians in the critical care setting, such as the reluctance to change an antibiotic regimen that was proven to be effective, clinically deteriorating patients, lack of microbiological data or lack of confidence in the obtained culture and sensitivity results, fear or poor understanding on how to de-escalate, and the controversial data about its effectiveness and safety17. The severity of the patient’s illness and presence of drug resistance also influence the decision making in antibiotic de-escalation implementation due to the potential complications involved16,18. In addition, physician also faced 25 difficulties in de-escalating the broad spectrum antibiotics in the case of polymicrobial infection18. In this study, we prospectively assessed the frequency of antibiotic de-escalation and clinical impact of the de-escalation in terms of length of hospitalisation in medical wards of Penang General Hospital. We also identified the reasons of the physicians in the medical wards for not performing antibiotic de-escalation.
Methods This prospective and observational study included patients of any gender, aged more than 18 years old and admitted to the three medical wards (General Medical ward, Endocrinology & Neuromedical ward and Nephrology ward) of Penang General Hospital from July to September 2017. The inclusion criteria were patient who was given empiric broad spectrum antibiotics, and had positive culture and sensitivity results from laboratory. Patients who did not receive empiric antibiotics, those whom 25 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 infection was not suspected, with negative culture and sensitivity test from the laboratory, discharged home or deceased before the result of culture and sensitivity test was released, or transferred from the medical wards to other wards were excluded. Patients were recruited by universal sampling method. Patients with positive culture and sensitivity result were identified from the laboratory, and their case notes were reviewed in respective wards within 48 hours after the result of culture and sensitivity test was released. Patients’ diagnosis, empiric antibiotics and start date, culture and sensitivity test results, de-escalation of antibiotics (yes / no), antibiotic administered and length of hospitalisation were recorded in the Empiric Antibiotic De- escalation Survey Data Collection Form. For those whose antibiotic dose was not de-escalated in 48 hours after the release of culture and sensitivity test result, Antibiotic Non-de-escalation Review Form was filled by the doctor-in-charge to state the factors that influenced his or her decision. All the physicians participated in this study gave their consent. The data was analysed using IBM Statistical Package for the Social Sciences (SPSS) version 21.0. Descriptive results of continuous variables were expressed as mean and standard deviation (SD). Variables were tested for their association with de-escalation using Chi-square test or Fisher's exact test for categorical data and independent t-test for numerical outcome variable. To assess the impact of de-escalation on the length of hospital stay, p-value were determined and reported.
Results Population description We reviewed the cases of 488 patients and 389 were excluded because they were discharged or deceased before the review date, transferred to non-medical wards, no empiric antibiotic started or the antibiotic used were not included in our research protocol (Figure 1). Ninety-nine patients with the average age of 58 years old were included in this study. Demographic data and infection-related data were presented in Table 1. Slightly more than half of the patients were male (51.5%, n=51) and the majority of patients were admitted to the Nephrology ward (46.5%, n=46). The most frequently prescribed empirical antibiotics were third and fourth-generation Cephalosporins (60.6%, n=60), followed by Piperacillin / Tazobactam (30.3%, n=30) and Carbapenems (9.1%, n=9). In the 99 included patients, the samples that were sent for culture and sensitivity analysis were blood samples (77%) (77 samples), tracheal aspirate (6.1%), urine (5.1%), swab at brachiocephalic (BCF) (4%), peritoneal fluid (3%), tissue (1%), pus (1%), broncho-alveolar (BAL) pathogen (1%) and sputum (1%).
De-escalation De-escalation was performed in 86.9% of included patients (n=86). Most of the de-escalation was performed in Nephrology Ward (51.2%, n=44). The General Medical ward and Endocrinology & Neuromedical ward had 38.4% (n=31) and 12.8% (n=11) of de-escalated patients respectively. Empirical antibiotics that was most frequently de-escalated was the cephalosporin group (60.4%, 26 n=52), piperacillin/tazobactam (29.1%, n=25) and carbapenem group (9%, n=9). The mean length of hospitalization with de-escalation of antibiotics performed was 15.4 days.
No de-escalation Out of the 99 patients, de-escalation was not performed in 13 patients. The non-de-escalated patients from General Medical ward was 53.8% (n=7), Endocrinology & Neuromedical ward was 30.8% (n=4) and Nephrology Ward was 15.4% (n=2). It was noted that cephalosporin group (61.5%, n=8) and piperacillin/tazobactam (38.5%, n=5) was the antibiotics that was not de-escalated. The reasons for no de-escalation were patient was clinically deteriorating (28%), fear of de-escalating in complicated patient (20%), immunocompromised patient (12%), lack of confidence in sampling quality or technique
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(8%), lack of confidence on laboratory culture and sensitivity result (12%), patient was clinically improving (4%), suspected polymicrobial infection (12%), and did not aware of culture result (4%). Outcome De-escalation was performed in 86.9% of culture-positive patients but it did not influence the length of stay of patients in medical wards, which were 15.4 days (SD 8.3) in de-escalation versus 14.0 days (SD 7.3) in no de-escalation (p=0.727).
Figure 1: Flow chart of study population inclusion and exclusion process
Patients evaluated for inclusion (n=488)
Excluded (n=389) - discharged before review (159) - antibiotic not in protocol (120) - deceased before review (61) - transferred to non-medical ward (37) - no empiric antibiotic (12) Included (n=99)
De-escalation No de-escalation (n=86) (n=13)
Table 1: Characteristics and patients’ outcome according to the therapeutic strategy Characteristics All De-escalation No de-escalation p-value Overall, n (%) 99 86 (86.9) 13 (13.1) Age, mean (SD) 58.6 (14.3) 58.0 (14.6) 61.5 (12.2) 0.481a Gender, n (%) 0.763b Male 51 (51.5) 45 (45.4) 6 (6.1) Female 48 (48.5) 41 (41.4) 7 (7.1) Ward, n (%) 0.040c General Medical 38 (38.4) 31 (31.3) 7 (7.1) Endocrinology & Neuromedical 15 (15.2) 11 (11.1) 4 (4.1) Nephrology 46 (46.5) 44 (44.4) 2 (2.0) Antibiotic group, n (%) 0.429c Cephalosporin 60 (60.6) 52 (52.5) 8 (8.1) Piperacillin/tazobactam 30 (30.3) 25 (25.2) 5 (5.1) 27 Carbapenem 9 (9.1) 9 (9.1) 0 Length of stay, days, mean (SD) 15 (8.2) 15.4 (8.3) 14.0 (7.3) 0.727a a Independent t-test; b Chi-square test; c Fisher’s Exact Test
Discussion This single-centre prospective study demonstrated that 86.9% of patients in the Medical wards had their antibiotics de-escalated. Our finding was almost similar to Liu et al. that reported the rate of de- escalation was 73% in their retrospective study of 240 patients19. Nonetheless, studies focusing on specific subgroups of patients gave various results. The de-escalation ranged from 6% to 74% in
27 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 patients with ventilator-associated pneumonia and was 34.9% in patients with severe sepsis or septic shock14,15. Most of the studies on antibiotic de-escalation were confined to the intensive care setting and were disease-specific. For example, a randomised, prospective trial by Singh et al., in 81 patients in the intensive care unit with ventilator-associated pneumonia whose antibiotics was de-escalated were less likely to develop antibiotic resistant super-infections compared to those whose regimen was not de-escalated20. In addition, an observational prospective study by Giantsou et al. involving 143 ventilator associated pneumonia patients demonstrated decreased mortality with shorter ICU and hospital stay in patients whose antibiotic regimens were de-escalated21. Nevertheless, a study by Moraes et al. reported that among the 224 patients with severe sepsis and septic shock, de- escalation was performed in only 44 patients (19.6%)22. Another study by Turpkaet et al. stated that among 283 suspected pneumonia requiring mechanical ventilation patients, antibiotics in 140 (49%) patients were de-escalated23. These studies were done mostly on critically-ill patients in non-medical wards. From 488 culture positive patients, 389 (79.7%) were excluded in our study. One of the reasons of high exclusion rate was due to the patients being discharged early before the review date. These patients may have improved clinically and conversion of intravenous to oral antibiotics was possible. A study by Liu et al. has also excluded those patients who were discharged early from the review date19. Short duration of injection use (around two days) followed by oral medications to complete the course of therapy would benefit many patients (except in certain conditions such as life- threatening infections, in critically ill patients, or in the presence of contraindications to oral administration) as it would reduce the length of hospital stay and the risk of hospital acquired infection26. Bacterial culture is the best method for diagnosis of infection but it does not indicate the host’s response or differentiate between bacterial colonisation and systemic complications. In addition, it takes more than 24 hours to get the result. Markers like procalcitonin (PCT) or C-Reactive Protein test (CRP) respond to both infection and inflammation, and reflect both microbiological findings and the host response, which have significant influence on the prognosis and outcome. PCT is stable in blood samples, easy to perform, not too expensive, and provides a quick answer (30 minutes for automated PCT assay on Kryptor using TRACE technology and more sensitive than the luminometric assay). Meta-analysis done by Uzzan et al. showed that PCT had a greater accuracy than CRP in this context27. As a screening test, PCT could help decide which patients were likely to have infection and thus should be offered multiple cultures and empirical antibiotic therapy. Increased PCT also indicated a systemic inflammatory host response to infection, probably endangering the patient by an increased risk of organ dysfunction27. Thus, biomarkers can be a complementary method to improve the practice of de-escalation of antibiotics. Study by Shafazand et al. documented that up to 50% of positive cultures might be sample contamination in critically ill patient28. Positive microbial cultures in critically ill patients often prompt 28 reflexive antimicrobial therapy, regardless of the sampling site or the contamination potential. Specifically, positive "sterile site" cultures (such as blood cultures) better represente true infection than positive "non-sterile site" cultures (such as wound cultures). Non-sterile sites were more likely to be colonisation or contamination. Appropriate antimicrobial use should preferentially be based on positive cultures from the sterile sites rather than from non-sterile sites. Distinguishing between contamination and true positives can be difficult, and clinicians may benefit from AMS assistance with regimen choice and education surrounding contamination potential28. AMS education programme on proper sampling technique with multiple sets of blood culture taken may improve the confidence of doctors on the sampling technique and results. Immediate microbiology laboratory reporting to wards on positive blood cultures should be encouraged as most therapy interventions occurred after notification of results. By doing so, it may be possible to establish a framework for the improvement of test result 28 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 communications that heeds the dual requirements of patient-centred care and logistical constraint, consequently improving the frequency of antibiotic de-escalation. This study was only conducted for three months due to the time constraint thus smaller sample size was enrolled. Therefore in future it is encouraged to conduct this study for longer period of time in order to enrol more patients. In this study, only three medical wards were included. For example, the General Medical ward is an acute ward with limited beds and shorter hospital stay. The frequently used broad spectrum antibiotics such as Unasyn® and Augmentin® were excluded from this study. Therefore, more wards, especially critical ward (Intensive Care Unit), Surgical, Orthopaedic or Obstetrics and Gynaecology (O&G) wards, where patients need longer hospitalisation and with higher utilisation of empirical antibiotics should be enrolled. In addition, the study did not evaluate the appropriateness of antibiotics in both empiric and de-escalated regimens. In this study, we focused only on the de-escalation practice of antibiotics. Nevertheless, this study may serve as a benchmark and path for future study in this area. Antibiotic de-escalation is a key function of AMS. The implementation of AMS may facilitate the implementation of antibiotic de-escalation24,25. As a result, the frequency of de-escalation observed in this study was higher than no de-escalation. However, our study did not compare the frequency of antibiotic de-escalation before and after the establishment of the AMS. Rather, it assessed the antibiotic de-escalation practice with the aim of providing a benchmark for other institutions with AMS. Future studies could compare the practice of antibiotic de-escalation with and without established AMS.
Conclusion The percentage of antibiotic de-escalation in the medical wards of Penang General Hospital was high. The length of hospital stay did not differ between patients with or without antibiotic de-escalation. Clinical worsening of patients despite antibiotic therapy was the most common reason for not performing de-escalation. This study may serve as a precedent to introduce AMS with antibiotic de- escalation to other disciplines or wards to help tackle the increasing AMR rate.
Acknowledgement The authors would like to express their gratitude to the Director General of Health for his permission to publish this article and to those who contributed directly or indirectly in this study.
Conflict of Interest Statement No external funding was received and the authors declared no conflict of interest.
References 1. Antimicrobial resistance [Online]; World Health Organization, 2017. http://www.who.int/ mediacentre/factsheets/fs194/en/ (accessed March 26, 2017). 29 2. Filice, G.; Nyman, J.; Lexau, C.; Lees, C.; Bockstedt, L.; Como-Sabetti, K. Excess Costs and Utilization Associated with Methicillin Resistance for Patients with Staphylococcus aureus Infection. Infection Control & Hospital Epidemiology. 2010, 31(04), 365-373. 3. Ventola, CL. The Antibiotic Resistance Crisis: Part 2: Management Strategies and New Agents. Pharmacy and Therapeutics. 2015, 40(5), 344-352. 4. Ventola, CL. The Antibiotic Resistance Crisis. Pharmacy & Therapeutics. 2015, 40(4), 277–283. 5. National Surveillance of Antibiotic Resistance (NSAR) Report [Online]; Institute of Medical Research, Ministry of Health Malaysia. 2015. http://www.imr.gov.my/en/component/ content/article/75-english-content/national-collabration/1469-nsar-main.html (accessed March 28, 2017)
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6. National Antibiotic Guideline (NAG), 2nd Edition [Online]. Pharmaceutical Services Divisions. 2014. http://www.pharmacy.gov.my/v2/en/documents/national-antibiotic-guideline- nag-2nd- edition.html (accessed March 27,2017) 7. Protocol on Antimicrobial Stewardship Program in Healthcare Facilities, 1st Edition. Pharmaceutical Services Division. 2014. 8. Madaras-Kelly, K.; Jones, M.; Remington, R.; Hill, N.; Huttner, B.; Samore, M. Development of an Antibiotic Spectrum Score Based on Veterans Affairs Culture and Susceptibility Data for the Purpose of Measuring Antibiotic De-Escalation: A Modified Delphi Approach. Infection Control & Hospital Epidemiology. 2014, 35(09), 1103-1113. 9. Morel, J.; Casoetto, J.; Jospé, R.; Aubert, G.; Terrana, R.; Dumont, A. De-escalation as part of a global strategy of empiric antibiotherapy management: A retrospective study in a medico-surgical intensive care unit. Critical Care. 2010, 14(6), R225. 10. Singh, N.; Rogers, P.; Atwood, CW.; Wagener, M.M.; Yu, VL. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription. Am J Respiratory Critical Care Medicines. 2000, 162, 505- 511. 11. Kollef, MH.; Morrow, LE.; Niederman, MS.; Leeper, KV.; Anzueto, A.; Benz-Scott, L.; Rodino, FJ. Clinical characteristics and treatment patterns among patients with ventilator-associated pneumonia. Chest. 2006, 129, 1210-1218. 12. Giantsou, E.; Liratzopoulos, N.; Efraimidou, E.; Panopoulou, M.; Alepopoulou, E.; Kartali- Ktenidou, S.; Manolas, K. De-escalation therapy rates are significantly higher by bronchoalveolar lavage than by tracheal aspirate. Intensive Care Med. 2007, 33, 1533-1540. 13. Heenen, S.; Jacobs, F.; Vincent, JL. Antibiotic strategies in severe nosocomial sepsis: why do we not deescalate more often? Critical Care Med. 2012, 40, 1404–1409. 14. Garnacho-Montero, J.; Gutie´-rrez-Pizarraya, A.; Escoresca-Ortega, A. Deescalation of empirical therapy is associated with lower mortality in patients with severe sepsis and septic shock. Intensive Care Med. 2014, 40, 32–40. 15. Madaras-Kelly, K.; Jones, M.; Remington, R.; Caplinger, C.; Huttner, B.; Jones, B. Antimicrobial de-escalation of treatment for healthcare-associated pneumonia within the Veterans Healthcare Administration. Journal of Antimicrobial Chemotherapy. 2015, 71(2), 539-546. 16. Salahuddin, N.; Amer, L.; Joseph, M.; El-Hazmi, A.; Hawa, H.; Maghrabi, K. Determinants of Deescalation Failure in Critically Ill Patients with Sepsis: A Prospective Cohort Study. Critical Care Research and Practice. 2016, 2016, 1-7. 17. Garnacho-Montero, J.; Escoresca-Ortegaa, A.; Ferna´ndez-Delgado, E. Antibiotic de-escalation in the ICU: how is it best done?. Current Opinion Infectious Disease. 2015, 28(2), 193–198. 18. Tabah, A.; Cotta, M.; Garnacho-Montero, J.; Schouten, J.; Roberts, J.; Lipman, J. A Systematic Review of the Definitions, Determinants, and Clinical Outcomes of Antimicrobial De-escalation in the Intensive Care Unit. Clinical Infectious Diseases. 2015, 62(8), 1009-1017. 30 19. Liu, P.; Ohl, C.; Johnson, J.; Williamson, J.; Beardsley, J.; Luther, V. Frequency of empiric antibiotic de-escalation in an acute care hospital with an established Antimicrobial Stewardship Program. BMC Infect Dis. 2016, 16(1), 751. 20. Singh, N.; Rogers, P.; Atwood, CW. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit: a proposed solution for indiscriminate antibiotic prescription. Am J RespirCrit Care Med. 2000, 16, 505–511. 21. Giantsou, E.; Liratzopoulous, N.; Efraimidou, E. De-escalation therapy rates are significant higher by bronchoalveolar lavage than by tracheal aspirate. Intensive Care Med. 2007, 33, 1533–1540. 22. Moraes, R.B.; Guillén, JAV.; Zabaleta, WJC.; Borges, FK. De-escalation, adequacy of antibiotic therapy and culture positivity in septic patients: an observational study. RevistaBrasileira de terapiaintensiva. 2016. 28(3), 315-322. 30 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018
23. Trupka, T.; Fisher, K.; Micek, ST.; Juang, P.; Kollef, MH. Enhanced antimicrobial de-escalation for pneumonia in mechanically ventilated patients: a cross-over study. Critical Care. 2017, 21(1), 180. 24. Lesprit, P.; Brun-Buisson, C. Hospital antibiotic stewardship. Curr Opin Infect Dis. 2008, 21, 344– 349. 25. Patel, D.; Lawson, W.; Guglielmo, BJ. Antimicrobial stewardship programs: interventions and associated outcomes. Expert Rev Anti-Infect Ther. 2008, 6, 209–222. 26. Septimus, E.J.; Owens, RC. Need and potential of antimicrobial stewardship in community hospitals. Clinical infectious diseases. 2011, 53(1), 8-14. 27. Uzzan, B.; Cohen, R.; Nicolas, P.; Cucherat, M.; Perret, GY. Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: a systematic review and meta-analysis. Crit Care Med. 2006, 34(7), 1996-2003. 28. Shafazand, S.; Weinacker, AB. Blood cultures in the critical care unit. Chest. 2002, 122, 1727- 1736. 29. First Notification of Positive Blood Cultures and the High Accuracy of the Gram Stain Report. Sogaard, M.; Norgaard, M.; Schonheyder, H. 2017.(accessed March 28, 2017). 30. Detection and Treatment of Bloodstream Infection: Laboratory Reporting and Antimicrobial Management. Munson, E.; Diekema, D.; Beekmann, S.; Chapin, K.; Doern, G. 2017. (accessed March 27, 2017). 31. Gonzalez, L.; Cravoisy, A.; Barraud, D.; Conrad, M.; Nace, L.; Lemarié, J.; Gibot, S. Factors influencing the implementation of antibiotic de-escalation and impact of this strategy in critically ill patients. Critical Care. 2013, 17(4), R140.
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The Impact of Epilepsy Review Service on Seizure Control in Primary Care
Wong Su Li1, Cheang Ching Ye1, Norharlina Sulaiman1, Hanum Maisarah Abdul Rahman1, Ng Kar Mun1
1 Klang District Health Office, Selangor State Health Department, Ministry of Health Malaysia
Abstract
Introduction: Epilepsy is a debilitating disease affecting more than 200,000 people in Malaysia. Only 9.6 per cent (%) of epilepsy patients had their seizure well-controlled in our facilities. Epilepsy Review Service (ERS) was initiated to improve health outcomes among epilepsy patients. Objective: The primary objective of the study was to evaluate the impact of ERS on seizure control in patients with epilepsy after implementing ERS. Methods: A comparative, non-controlled study on epilepsy patients attending government health clinics in Klang district was conducted over a period of 12 months. All eligible and consented patients were enrolled into ERS at the point where baseline data was collected. Patients were reviewed at 0, 6 and 12 months where interventions were undertaken by the healthcare team. Data was retrieved using a review form, Therapeutic Drug Monitoring (TDM) records, and patient self-reported seizure frequency before and after the interventions. Results: Data from a total of 156 patients was analysed. Before implementation of ERS, there was delayed completion of TDM cases (40.6%), lack of counselling related to epilepsy issues (21.8%), lack of review on medication side effects (5.1%) and drug interactions (20.5%). Post-intervention showed increments in the completion of TDM cases within 72 hours (84.1%), counselling done (89.3%), as well as review of medication side effects (77.9%) and drug interactions (82.1%). Seizure improvement among epilepsy patients increased from a baseline of 9.6% to 37.8% at 6 months and 52.6% at 12 months. The mean monthly seizure frequency of patients was significantly reduced from 1.91 (SD 2.02, range 0-7, median 1.0) at the end of 6-month post intervention to 0.94 (SD 1.30, range 0-7, median 1.0) at the end of 12-month post intervention (p <0.001). Conclusion: Pharmacist-initiated implementation of ERS has great potential in improving seizure control.
Keywords: pharmacist medication review, seizure control, primary care
NMRR ID: NMRR-14-1789-23732
32 Corresponding author: Wong Su Li Pharmacy Department, Klang District Health Office, Blok B, Jalan Langat, Bandar Botanic, 41200 Klang, Selangor. Email: [email protected]
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Introduction Epilepsy is one of the common neurological disorders seen in primary care. The World Health Organization (WHO)1 reported that patients with epilepsy (PwE) have up to 3 times higher risk of premature death and there are significant economic implications due to health care expenses and loss of productivity. In Malaysia, it was estimated that more than 200,000 people suffer from epilepsy in which anti-epileptic drugs (AEDs) remain the cornerstone of epilepsy treatment2,3. With effective management, up to 70% of people with active epilepsy have the potential to become seizure-free4,5,6. Primary healthcare services should focus on continuity of care for stable PwE who have been discharged from tertiary care7. A study conducted in the United Kingdom (UK) showed that a structured review process for epilepsy in primary care has been advocated as the best practice in providing quality care8. Majority of the patients felt that pharmacists’ review was good, helped improving the understanding of their condition, and was informative and reassuring. In our current setting of Ministry of Health (MOH) health clinics in Klang district, state of Selangor, Malaysia, pharmacists have established review services for patients with common chronic conditions (e.g., diabetes, asthma) but not epilepsy. We found a lack of structured framework in managing PwE with several shortfalls such as poor documentation, lack of efficiency of therapeutic drug monitoring (TDM) service and epilepsy-related counselling. Prior to any interventions, it was found from our initial survey that only 9.6% of PwE had their seizure well controlled in all outpatient clinics in the district. Therefore, we established the Epilepsy Review Service (ERS) to improve the quality of care to PwE. ERS is a pharmacist-led service which consists of three components: clinical assessment and documentation, improvement in TDM service, and individualised epilepsy counselling. Through ERS, we review PwE at least once a year, improve the standard of TDM service, and provide individualised epilepsy counselling during their follow-up appointments. Our project aimed to assess the outcome of ERS and its potential in improving seizure control and the overall management of epilepsy patients in primary care.
Methods Design and setting This was an experimental, comparative, non-controlled study conducted over a period of 12 months in three phases. This study comprised of an intervention period and two observational periods. Baseline data collection was conducted from January 2014 till March 2014. This was then followed by a 3- month intervention period from April 2014 to June 2014. The first assessment was conducted from July 2014 to September 2014. The second assessment was then performed from October 2014 till December 2014 using the same data collection tool. All pharmacists and other healthcare providers were given education sessions on Epilepsy, AED, TDM and ERS implementation. Standardised workflow of care, TDM guide and epilepsy counselling guide were distributed among the team members. The ERS team met once a month within the course of intervention for discussion and 33 ensuring the progress of ERS implementation.
Participant recruitment Prior to the enrolment, we established an epilepsy registry by screening all PwE attending outpatient pharmacy. Patients who fulfilled the criteria of having a clinical diagnosis of epilepsy, taking at least one type of AED, and attended regular follow-up appointments at our clinics were registered. Patients below 18 years of age, on temporary referral to the clinic, or having follow-up appointments at a tertiary care setting were excluded. We introduced ERS to PwE by explaining to them the expected objectives of this newly implemented service. Verbal informed consent was obtained from patients or their caregivers. This research was conducted according to the World Medical Association (WMA) Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects. 33 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018
Data collection Consented patients were interviewed and their baseline seizure frequencies were documented in a self-constructed ERS record form within a period of three months. Baseline AED level monitoring, medication understanding and compliance were assessed and issues on medication side effects and other medication safety issues were identified and recorded. Subsequently, remedial actions were taken and patient monitoring was continued for another three months with appointment intervals scheduled according to individual patient need. All patients were given education on how to identify the frequency, type, duration and possible triggers of their seizure, and how to record them. Specially designed seizure diaries were distributed to the patients and standard instructions on diary recording were given. Patients were interviewed in the next encounter and their follow-up seizure frequencies were recorded in the ERS record form. In order to evaluate ERS as a new service, quality indicators as shown in Table 1 were adapted from Quality Indicators in Epilepsy Treatment Tool (QUIET) tools (Chronic Epilepsy Care Section)9 published by the Agency for Healthcare Research and Quality (AHRQ), USA and standards for each indicator were set. Only tools numbered 11 to 16 as shown in Appendix 1 that suit the primary care setting practice and resources were selected. We also adapted three other indicators that were deemed important in measuring quality of TDM service.
Table 1: ERS quality indicators Indicators Descriptions All epilepsy patients are interviewed and data documented at each visit regarding: Review for epilepsy Number of seizures Types of each seizure episode Drug side effects experienced ̵ Request baseline TDM level for all PwE ̵ All TDM ordering should achieve: Improve TDM service TDM request completed within 72 hours Acceptance of TDM Case Interpretation & Recommendation by Medical Officers (MO) All epilepsy patients are given individualised epilepsy counselling at least once a year: Provide individualised Seizure Diary epilepsy counselling Safety advice Lifestyle advice Medication interactions and side effects review
34 Data analysis In this study, we evaluated the impact of ERS in improving seizure control and measured the percentage of patients who had improvement in seizure control through seizure frequency reduction. The difference in seizure frequencies pre- and post-intervention was computed and accounted as reduction or increment in seizure frequency. The standard end point in clinical trials and clinical practice worldwide outlined a 50% reduction in seizure frequency from the baseline to indicate improvement in seizure control10,11,12. This indicator was selected as our primary outcome. The number and demographic characteristics of patients attending ERS appointments at baseline, at 6-months and at 12-months period respectively were expressed as frequencies and percentages. Differences in the indicator achievement were analysed and described accordingly. As for the seizure frequency, the data were expressed as the mean and standard deviation (SD). 34 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018
Wilcoxon signed rank test was used to compare the mean seizure frequency at baseline, at 6-months and 12-months, comparing before and after interventions at 6-monthly interval respectively. Data were analysed using the Statistical Package for Social Sciences (SPSS) 22.0. The significance level was fixed at 95% confidence interval.
Pharmacist-based interventions The intervention period was divided into two parts. The first part was intended to improve the process of epilepsy care through workflow restructuring and the empowerment of both pharmacists and prescribers. The epilepsy patient registry was established and ERS record form was designed and used by all pharmacists with the aim to produce systematic and accessible information on patient disease progress during their follow-up appointments. In our centre, TDM for epilepsy patients were done on patients on AEDs therapy such as Sodium Valproate, Carbamazepine, Phenobarbitone and Phenytoin. TDM is well accepted as an objective measure of patient adherence towards medication prescribed, monitoring of drug toxicity and adverse drug reaction13. In this phase, prescribers were encouraged to use existing TDM services managed by the pharmacists. Prior to the interventions, prescribers were not well aware of the availability and accessibility of TDM service. A standardized ERS TDM Guide which consists of a compact-sized quick reference on TDM sampling times for TDM and the therapeutic range were distributed for prescribers. A checklist of patients’ situation in which TDM need to be ordered was also included in the guide. Empowerment of pharmacists was also emphasised in this phase where training and workshops were conducted to standardised TDM results calculation and interpretation. To this end, a Microsoft Excel worksheet with pre-set calculations was constructed to ease counterchecking of pharmacokinetic calculations and interpretations. In the second part, the focus was to establish patients’ awareness and knowledge about their disease. There was no standardized counselling or education materials regarding epilepsy self- management and medication given to patients in our setting prior to the intervention. The seizure diary that was distributed to each patient or caregiver contains diagrammatical explanation on AEDs, adverse reactions and interactions, and how to handle a patient experiencing a seizure. Using the seizure diary as counselling aid, pharmacists gave counselling on these aspects to the patients when distributing the diary. Medication counselling was given to patients based on the ERS Epilepsy Medication Counselling Guide by trained pharmacists. The pharmacists provide individualised medication counselling based on patients’ level of understanding, compliance and other drug related problems. They also gave an overview about safety and injury advice, lifestyle advice, family planning and contraception as well as other epilepsy-related issues. The content of all documents and guides used in ERS were developed by the team member based on current references and guidelines and validated by 3 expert panels within the district that are not the group member of the study. 35
Results Patient characteristics A total of 254 patients with epilepsy registered in the clinic were screened and 203 of them were enrolled based on our inclusion and exclusion criteria. The final number of patients enrolled in ERS stands at 156 patients after 47 more patients were excluded due to the following reasons; transferred to other care setting (n=16), unable to be contacted (n=10), refused to join ERS (n=12), and other reasons (n=9). In terms of racial composition, Indians made up 40.3% (n=63), followed by 33.9% Malays (n=53), and 25.8% Chinese (n=40). The demographic characteristics of the study population were shown in Table 2.0.
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ERS quality indicators Measurement of improvement based on Epilepsy Review Service (ERS) components adopted from Quality Epilepsy Indicator Tool (QUIET)9 was shown in Table 3.
Seizure control The seizure control improvement among PwE was presented in Figure 1. We found that the percentage of PwE achieving at least 50% reduction in seizure frequency increased from a baseline of 9.6% to 37.2% at the end of 6-month, and 52.6% at the end 12-month period. The mean monthly seizure frequency dropped from 1.95 (SD 2.04, range 0-10, median 1.0) at the baseline to 1.91 (SD 2.02, range 0-7, median 1.0) at 6 months and the reduction was not significant (p=0.635). However, the mean monthly seizure frequency of patients was significantly reduced from 1.91 (SD 2.02, range 0-7, median 1.0) at the end of 6-month post intervention to 0.94 (SD 1.30, range 0-7, median 1.0) at the end of 12-month post intervention (p <0.001).
Table 2: Demographic characteristics of the study population Characteristics n (%) Age, mean (SD) 52.21 (15.75) range 20 - 75 Gender, n (%) Male 84 (53.9) Female 72 (46.1) Ethnicity, n (%) Malay 53 (33.9) Chinese 40 (25.8) Indian 63 (40.3)
Table 3: Measurement of improvement based on components of ERS Percentage of patient, % ERS component Indicators Before ERS After ERS 0-month 6-month 12-month
Number & type of seizure 8.3 65.40 97.9 Review for epilepsy Drug side effects 5.1 55.70 77.9
Request baseline TDM level for all PwE 43.6 55.40 80.7 36 Improve TDM TDM results informed within 72 hours 40.4 62.50 67.9 service Acknowledgement of TDM interpretations and 41.7 67.80 70.7 recommendations by MO Provide seizure diary 0 65.40 96.4 Provide Provide safety advice 2.6 55.70 83.6 individualised epilepsy Provide lifestyle advice 21.8 55.40 89.3 counselling Review medication interactions and side 20.5 62.50 82.1 effects
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Figure 1: Percentage of PwE achieving at least 50% reduction in seizure frequency and mean monthly seizure frequency at 0, 6 and 12 months (n=156)
1.94 100% 1.91 2
90% 80% 1.5
70%
60% 0.94* 50% 1
40% % of % Patients 30% 0.5 20%
10% Mean Monthly Seizure Frequency 9.6% 37.2% 52.6% 0% 0 0-month 6-months 12-months Duration Percentage of Patients Achieving Reduction in Seizure Frequency Mean Monthly Seizure Frequency
* statistically significant reduction of mean seizure frequency from month 6 to month 12 (p < 0.001)
Discussion Pharmacists-led ERS interventions resulted in reductions in seizure frequencies, signifying improvement in seizure control. Through the implementation of ERS, we found that the longer the follow-up duration with ERS, better improvement can be attained in patients’ seizure control. Positive observations as such were also the findings from previous studies abroad on structured care of PwE8,14. There was a need to address issues in epilepsy patient management, improvement in TDM service and provision of individualised patients’ counselling at the primary care level. From the pre- remedial findings, poor documentation was identified and there was a lack of medication review for epilepsy patients. Pharmacists can play a major role in implementing structured epilepsy patient review and work together with other healthcare providers in a multi-disciplinary approach to ensure sustainability of the service. 37 Pharmacists in our setting were occupied with the role of dispensing most of the times. There was no standard epilepsy counselling guide or specific encounter scheduled for epilepsy patients for pharmacist’s review. Through ERS, the competency of pharmacists in managing epilepsy patients has greater potential for improvement. ERS pharmacists can now provide individualised epilepsy counselling and manage TDM cases better using the guides provided. In addition, patients should be regularly reviewed (at least once a year) by pharmacists so that issues related to disease management such as lifestyle and safety issues can be resolved in a timely manner. With continuous review, patients and caregivers are better empowered and motivated to self-manage their condition8,15. The current practice for TDM service varies from one clinic to another and it affects the efficiency of service provided. Before implementing ERS, we discovered that the availability of baseline TDM level was recorded in only less than half of the patients. Additionally, only half of TDM
37 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 results were informed and acknowledged to prescribers within 72 hours. This was due to the current practice of informing prescribers of the TDM results during the patient’s next appointment; and only upon request. To ensure that patients receive the optimum dose for their AEDs, TDM results should be communicated to prescribers within 72 hours. ERS has improved the efficiency of TDM service, whereby the time to inform, interpret and intervene TDM cases to prescribers had been shortened from 3 months to a standard of 72 hours. This is important as to ensure that the decision of dosage adjustment related to AEDs could be carried out promptly especially in toxic cases16. Epilepsy patients were seen by different prescribers each time they came for their follow-up appointments. We observed inconsistencies in the recording of patients’ medical progress especially in terms of number and types of seizures, side effects of AED, and other related information. This led to difficulty to trace and understand patient’s condition as a whole. Importance of documentation should be emphasized for better continuity of care for these patients17, and this was established in ERS implementation. The newly-designed Seizure Diary served as a useful tool for patients, pharmacists and prescribers. Patients and their caregivers were able to record the seizure frequency systematically and thus have better understanding to self-manage their conditions. In our view, pharmacists can monitor patients’ condition and further assist prescribers to better manage patients’ seizure episodes, disease control and optimisation of AEDs dosages and this was also supported by the findings of Halls et al.18. Furthermore, the diary also served as a medium for information transfer between primary, secondary and tertiary care or between public and private healthcare services especially in emergency, walk-in visits or unplanned admission to the wards. Hence, ERS has strengthened the communication between prescribers and pharmacists in handling epilepsy patient care and bringing benefits to the patients. The ERS was implemented in order to provide better service for our epilepsy patients. We also believed that there will be different or possibly even better management of epilepsy patients in other primary care settings. It requires support from tertiary care settings in the form of advice and timely referral to ensure complicated epilepsy cases are managed appropriately. The current study measured seizure control based on patient self-reported seizure frequency. Data was presumed to be accurately reported by the patient as a trustworthy source of data. Although actual seizure frequency may be poorly reported by patients, their ability to estimate and document their seizure frequency should not be ignored19,20,21. The number of hospital admissions, emergency visits or electroencephalogram would serve as a more objective clinical outcomes measurement. There were patients whom did not attain seizure control from our optimised care due to the nature of the disease22. The seizure frequency in these patients had been increased, unchanged or had less than 50% reduction throughout the study period. This preliminary finding proposed a repeated study with a control group to prove the effectiveness of the intervention. As ERS was implemented to all our patients as a service improvement, there was no group of patients without ERS intervention that can be assigned as control. Other issues that could be important concerns to address in future studies 38 would be interventions on patient’s compliance and cost-economic aspects of ERS implementation. As the ERS is still novel in our health care setting, there are still room for improvement to achieve better patient care and quality of life. Since the study was only conducted in a single setting, the findings may not represent the whole Malaysian population of PwE.
Conclusion The project team has identified gaps in PwE management in primary care. This problem was addressed through the implementation of ERS as an intervention, and has thus far led to the improvement of seizure control in most of our patients. Our study suggested implementation of ERS can lead to improvement in seizure control through seizure frequency reduction over time. Continuous education sessions need to be arranged to ensure competency of the healthcare personnel involved. 38 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018
An audit team shall be established in the future to ensure continual compliance to the improved standard of care. The project team will also carry out proactive approaches to address any issues regarding the service in a timely manner as well as enhancing the awareness of the epilepsy services provided within the primary care setting.
Acknowledgement We would like to thank the Director General of Health, Ministry of Health Malaysia for the study approval with National Medical Research Registration Identity (NMRR-14-1789-23732) to conduct this study in Malaysia and his approval to publish this article. We would also like to thank the Dr. Haji Che Azlan Shah bin Shahari, the Director of Klang District Health Office (DHO), Madam Nor Azlina binti Sariam, the Head of Pharmacy of Klang DHO, Dr. Goh Pik Pin from the National Clinical Research Centre (NCRC) and Prof. Low Wah Yun from the University of Malaya for their tireless support and commitment in contributing their time and resources to make this publication possible.
Conflict of Interest Statement No external funding was received and the authors declared no conflict of interest.
References 1. World Health Organisation 2017; Epilepsy: epidemiology, aetiology and prognosis. WHO Factsheet, February 2017, number 165. 2. Health Grades Inc: Statistic by country for Epilepsy. 2011, http://www.rightdiagnosis.com/e/epilepsy/stats-country.htm (accessed February 28, 2016). 3. Zakaria, AK. Principles of treatment of epilepsy. Malaysian J Med Sciences. 1998, 5(1), 11-17. 4. Guekht, A. Debate: A 50% reduction in seizure frequency is a useful measure to assess treatment response in epilepsy. [online] 2010. http://comtecmed.com/cony/2011/Uploads/assets/guekht_epilepsydebate6.pdf (accessed July 7, 2016). 5. Lambert, MV.; Bird, JM. The assessment and management of adult patients with epilepsy: the role of general practitioners and the specialist services. Seizure. 2001, 10, 341-346. 6. Sander, JW. The use of anti-epileptic drugs: principles and practice. Epilepsia. 2004. 45(6), 28-34. 7. Royal College of Physicians for Ireland 2016. The National Clinical Programme for Epilepsy. Version 20.p.20-29 8. Brown, C. Improving quality of care of epilepsy patients through a pharmacist review service. Progress in Neurology and Psychiatry. 2012, October, 12-18. 9. AHRQ (Agency for Healthcare Research and Quality) Quality Indicators in Epilepsy Treatment Tool. 2014. https://innovations.ahrq.gov/qualitytools/quality-indicators-epilepsy-treatment-tool (accessed February 28, 2016). 10. Guekht, A. Debate: A 50% reduction in seizure frequency is a useful measure to assess treatment 39 response in epilepsy. [online] 2010. http://comtecmed.com/cony/2011/Uploads/assets/guekht_epilepsydebate6.pdf (accessed July 7, 2016). 11. Birberk, G. Hays, RD.; Cui, XP.; Vickrey, BG. Seizure control and quality of life improvements in people with epilepsy. Epilepsia. 2002, 43(5), 535-538. 12. Cramer, JA.; French, J. Quantitative assessment of seizure severity for clinical trials: a review of approaches to seizure components. Epilepsia. 2001, 42(1), 119-129. 13. Clinical Pharmacokinetic Pharmacy Handbook. Ministry of Health Malaysia. Pharmaceutical Service Division. 2015. p.1-3, 22-32,96-103,148-157. 14. Groenewegen, A.; Tofighy, A.; Ryvlin, P.; Steinhoff, BJ.; Dedeken, P. Measures for improving treatment outcomes for patients with epilepsy: Results from a large multinational patient-physician 39 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018
survey. Epilepsy & Behavior. 2014, 34, 58–67. 15. Reis, TM.; Campos, M.; Nagai, MM.; Pereira. L. Contributions of Pharmacists in the Treatment of Epilepsy: A Systematic Review. Am J Pharm Benefits. 2016, 8(3), e55-e60 16. Monitoring Epilepsy : Epilepsy society factsheet 18. Epilepsy Society: [online] 2014, https://www.epilepsysociety.org.uk/monitoring-epilepsy-0 (accessed September 12, 2016). 17. Crozer Keystone Health System. Documentation: how important it is. January 2009. http://www.crozerkeystone.org/healthcare-professionals/medical-staff/physician- info/cme/articles/documentation/ (accessed October 13, 2016). 18. Hall, CB.; Lipton, RB.; Tennen, H.; Haut, SR. Early follow-up data from seizure diaries can be used to predict subsequent seizures in same cohort by borrowing strength across participants. Epilepsy & Behavior. 2009, 14, 472–475. 19. Hoppe, C.; Poepe,l A.; Elger, CE. Accuracy of patient seizure counts. Arch Neurol. 2007, 64(11), 1595-1599. 20. Neugebauer, R. Reliability of seizure diaries in adult epileptic patients. Neuroepidemiology. 1989, 8(5), 228- 233 21. Glueckauf, RL.; Girvin, JP.; Braun, JR.; Bochen, JL. Consistency of seizure frequency estimates across time, methods, and observers. Health Psychol 1990, 9(4), 427- 434. 22. National institute of neurological disorder and stroke 2016; The epilepsies and seizures: hope through research. http://www.ninds.nih.gov/disorders/epilepsy/detail_epilepsy.htm (accessed May 22, 2016).
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Appendix 1
QUIET | QUALITY INDICATORS IN EPILEPSY TREATMENT Adapted from AHRQ, 2014
CHRONIC EPILEPSY CARE 11. When a patient with epilepsy receives follow-up care, then an estimate of the number and types of seizures since the last visit and an assessment of drug side-effects should be documented. 12. When a patient with epilepsy receives follow-up care, then drug side-effects should be assessed and documented. 13. If the patient continues to have seizures after initiating treatment, then interventions should be performed. Options include: Compliance assessment/enhancement Monitor SM blood levels Increased SM dose Change SM dose Patient education regarding lifestyle modification Referral to higher level of epilepsy care 14. If a patient with epilepsy continues to have seizures after three months of care by a primary care provider, then further assessment by a neurologist should be conducted. 15. If a patient continues to have seizures after 12 months of appropriate care by a general neurologist, then the patient should receive a referral to an epilepsy specialist. 16. Patients with epilepsy should receive an annual review of information including topics such as: Chronic effects of epilepsy and its treatment including Drug side-effects, drug-drug interactions, and their effect on bone health, Contraception, family planning, and how pregnancy or menopause may affect seizures, Screening for mood disorders, Triggers and lifestyle issues that may affect seizures, Impact of epilepsy on other chronic and acute diseases, Safety issues (injury prevention, burns, driving restrictions, etc.) 41 Other patient self-management issues
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Evaluation of Utilisation and Concordance to Guideline-recommended Statin Therapy
at Medical Outpatient Clinic, Hospital Kuala Krai
Low Joo Zheng1, Ahmad Salihin Abdullah1, Nurul Azerah Idris1, Siti Noriah Muhd Yuna1, M. Irfan Ab Aziz1
1 Hospital Kuala Krai, Ministry of Health Malaysia
Abstract
Introduction: Hyperlipidaemia is one of major risk factors for atherosclerotic cardiovascular diseases (ASCVD), so appropriate treatment is crucial to prevent morbidity and mortality. Objective: The objective of this study was to evaluate the concordance of statin prescribing at medical outpatient clinic (MOPC), Hospital Kuala Krai to the 2013 ACC/AHA Guideline on the treatment of blood cholesterol, and to evaluate the therapeutic response of statin therapy. Methods: A retrospective observational study was conducted from February to August 2017 at MOPC, Hospital Kuala Krai. Calculated 10-year ASCVD risk was estimated using pooled cohort equation for all patients. Patients were then grouped into one of the four treatment indication groups in descending order of ASCVD risk. Patients were assigned to high intensity statin therapy, moderate intensity or statin not beneficial categories according to the guideline. The prescribed statin intensities were compared to the guideline recommended statin intensities to determine the concordance rate. Therapeutic responses, defaulted rate and adverse drug reaction (ADR) were also evaluated. Results: Overall, 106 patients were included in this study. The overall concordance rate was 43.4% with the highest in patient with clinical ASCVD (52.9%) and the lowest in patient with LDL-C ≥4.9 mmol/L (22.2%). Moderate-intensity statin therapy was most frequently prescribed (63.2%) in which 50.7% of these patients should have been treated with high-intensity statin therapy. A total of 28.9% of patients achieve targeted reduction in LDL-C. The default rate was 16.0% and one ADR was reported. Conclusion: The concordant rate to the 2013 ACC/AHA Guideline on the treatment of blood cholesterol was below satisfactory. Although the default rate was acceptable, the treatment response based on the prescribed statin intensities needs a lot of improvement.
Keywords: hyperlipidaemia, cholesterol, ASCVD risks, statins, 2013 cholesterol guidelines
NMRR ID: NMRR-18-1132-42084
Corresponding author: 42 Low Joo Zheng Department of Pharmacy, Hospital Kuala Krai, 18000 Kuala Krai, Kelantan. Email: [email protected]
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Introduction Over the decades, rapid urbanisation and modernisation along with changing lifestyles in Malaysia have left significant impacts on the general health of the population. While the nation experiences the reduction in communicable diseases, non-communicable diseases (NCD) such as cardiovascular diseases (CVD), diabetes mellitus and hypertension are on the rise. In Malaysia, NCD accounts for approximately 73% of total death1. In addition, death caused by CVD, particularly ischemic heart disease and stroke has been topping the list for the last decade2. Among the major risk factors for NCD are dyslipidaemia, hypertension, diabetes and obesity3. According to the National Health and Morbidity Survey (NHMS) 2015, the prevalence of hypercholesterolemia in adults age more than 18 years old was 47.7%, and 38.6% of this belongs to undiagnosed hypercholesterolemia4. This data is in fact worrisome as major health burden is expected for years to come. Several strategies have been implemented to tackle this issue which includes primary and secondary prevention of CVD. An observational study in Finland reported that reduction in major cardiovascular (CV) risk factors such as hypercholesterolemia, hypertension and smoking resulted in the reduction of observed CVD mortality5. Hence, this study aimed to focus on the usage of HMG-coA reductase inhibitor, or commonly known as statins, in the prevention of CVD. Numerous studies have shown that the usage of statins in primary and secondary prevention reduces CV events and CV mortality6. Unfortunately, inappropriate statin prescribing is still common in practice as it is often overprescribed or underutilised. Several studies have concluded that the overall concordance to practice guidelines was suboptimal, ranging from 50 to 60%7-9. A study in Ireland demonstrated that although the usage of statin has increased over the years, the prescribing rate according to guideline was still low10. In addition, a study in Saudi Arabia concluded that almost one third of their patients received statin inappropriately11. However, another study in the United States showed that overall concordance to the guideline was more than 50%12. We aimed to evaluate the utilisation of statins therapy among patients who followed up at the Medical Outpatient Clinic (MOPC) in Hospital Kuala Krai, Kelantan. The objectives of our study were: (1) to study the concordance of current statins prescribing to the 2013 American College of Cardiology / American Heart Association (ACC/AHA) Guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults13, (2) to determine the prevalence of CV events after statins therapy and to evaluate the treatment success rate and safety of statins therapy.
Methods Study design and subjects This retrospective study was conducted at the Medical Outpatient Clinic (MOPC), Hospital Kuala Krai, Kelantan, Malaysia from March 2017 to August 2017. The patients’ medical records from the date the first statin prescription was written to at least 3 months later were reviewed. The research was registered with the National Medical Registry Research Registry (NMRR) and approval to conduct the 43 research was obtained from the Medical Research and Ethics Committee (MREC). Patients who were initiated with statin monotherapy from year 2014 to 2016 were reviewed for study inclusion. Patients were randomly selected from the patient record centre at MOPC. The recorded systolic blood pressure (SBP) to the date as near as possible to the date of starting statin therapy was retrieved. Patients without baseline lipid profile tested before starting statin treatment were excluded from the study. Any patients whose statin therapy were started before year 2014 were excluded from this study because the ACC/AHA guideline on hyperlipidaemia treatment published on 2013 13 was used as a reference to determine the guideline concordance of statin prescribing pattern in MOPC. Due to the lack of statin intensity recommendation for patients younger than 40 years or older than 75 years, they were excluded from the study unless they have clinical atherosclerotic cardiovascular disease
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(ASCVD) or measured low-density lipoprotein cholesterol (LDL-C) level of ≥ 4.9mmol/L. In addition, patients with LDL-C concentration less than 1.8mmol/L without any clinical ASCVD were also excluded from the study. Also, any patient whose 10-years ASCVD risk could not be calculated (i.e. patients younger than 40 years or older than 79 years, with a high-density lipoprotein cholesterol (HDL-C) of < 0.5 mmol/L or > 2.6 mmol/L, with total cholesterol (TC) level of < 3.4 mmol/L or > 8.3 mmol/L or SBP < 90 mm Hg or > 200 mm Hg) were excluded from further evaluation. Any contraindication of statin therapy was assumed to have been reviewed by the prescriber before initiating statin treatment.
ASCVD risk estimation Estimation of 10-year ASCVD risk was calculated based on the pooled cohort equation for all patients using the ASCVD Risk Estimator14. This calculation was intended to aid healthcare providers in estimating the 10-year and life time risks of ASCVD. This calculation made use of patients’ age, gender, race, TC, HDL-C, SBP, use of blood pressure-lowering therapy, status of diabetes mellitus and smoking status to estimate the risk of developing ASCVD. Although initiation of statin therapy in patients for secondary prevention of ASCVD and LDL-C > 4.9 mmol/L was not required, the 10-year ASCVD risk was still calculated for all included patients in this study.
Patient categorisation After detailed evaluation of patients’ medical records, all included patients were divided into 4 groups, in descending order of ASCVD risk. Patients who required secondary prevention of ASCVD, i.e. those with documented history of acute coronary syndrome (ACS), coronary or other arterial revascularization, cerebral vascular disease (CVD) or peripheral artery disease, were placed in Group 1. Patients with LDL-C concentration > 4.9mmol/L were grouped in Group 2. Group 3 consisted patients who aged between 40 and 75 years with diabetes but without any previous history of ASCVD and had LDL-C concentration ranged between 1.8-4.8 mmol/L. Patients who aged from 40 to 75 years without history of ASCVD or diabetes with an LDL-C level of 1.8-4.8 mmol/L and calculated 10- years ASCVD risk ≥ 5% were assigned to Group 4.
Statin intensity and therapeutic goal After the 10-year ASCVD risk calculation and assignment to statin treatment benefit groups, the recommended intensity of statin therapy and therapeutic response were determined for each patient. The therapeutic response, expressed by percentage reduction from the baseline LDL-C concentration over at least 3 months of statin therapy was defined based on the recommended statin intensity. The patients were assigned to moderate intensity, moderate-high intensity, or high intensity based on the recommendation of the guideline13. These guideline-recommended statin intensities were then compared with the prescribed statin intensities received by the patients to assess guideline 44 concordance.
Outcomes assessment The primary objective of this study was to evaluate the concordance of statin therapy to the ACC/AHA Guideline on the treatment of blood cholesterol. In order to assess the guideline concordance, the prescribed statin therapies in the included patients were classified as high, moderate or low intensity and then compared with the suggested intensity in the guideline. The secondary objective was to assess the therapeutic response of statin therapy after at least 3 months of treatment. The therapeutic responses were achieved if the percentage reduction of LDL-C concentration from baseline were < 30%, 30-50%, > 50% in patients receiving low, moderate and high intensity statin therapy respectively. In addition, any adverse drug reactions due to statin therapy, defined as three times increases in
44 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 baseline AST/ALT level, complained of muscle pain at biceps / triceps, thorax or thigh muscles, were recorded. Any ASCVD or CVD that occurred after statin therapy and patient concordance to statin therapy were also assessed in this study.
Statistical analysis Statistical analysis for this study was conducted using Statistical Package for the Social Sciences (SPSS) software version 20. Normally distributed and skewed data were analysed using Student t-test and the Wilcoxon rank sum test respectively. Pearson’s chi-square test and Fisher’s exact test were used to analyse categorical data. For comparison of multiple groups of data, ANOVA test was used. A priori level of significance was set at < 0.05.
Results A total of 955 patients were treated with statins from year 2014 to 2016 at MOPC in Hospital Kuala Krai. Of these patients, 778 were excluded from the study because these patients were initiated with statin treatment before the publication of the ACC/AHA Guideline on the treatment of blood cholesterol in 2013. Then, 71 patients were also excluded from the final analysis because baseline profile lipid profiles were not recorded when they were started with statin therapy (Figure 1). Therefore, a total of 106 patients were included in this study.
Cohort Characteristic The majority of patients in this cohort were Malay (92.5%), and female patients made up almost half of the total patient population (Table 1). Over 50% of the patients in this study were also treated for diabetes (51.9%) or hypertension (54.7%). In addition, the overall mean baseline TC and LDL-C were 5.72 mmol/L (standard deviation (SD) 1.58) and 3.48 mmol/L (SD 1.29) respectively, which were higher than the recommended upper normal limit of TC < 5.2 mmol/L anf LDL-C < 2.6 mmol/L. Furthermore, the mean baseline SBP was also higher than the normal SBP of 120mm Hg. About one- third of the studied patient population were smokers while they were treated with lipid lowering agents.
Figure 1: Patient disposition
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Table 1: Baseline characteristics of study population All, Guideline Guideline Characteristic concordant discordant P-value n=106 prescribing, n=46 prescribing, n=60 Age, mean (SD) 57.6 (13.0) 59.9 (12.8) 54.5 (12.7) 0.192* Gender, n (%) 0.147# Female 50 (47.2) 18 (39.1) 32 (53.3) Male 56 (52.8) 28 (60.9) 28 (46.7) Race, n (%) 0.317# Malay 98 (92.5) 41 (89.1) 57 (95.0) Chinese 7 (6.6) 4 (8.7) 3 (5.0) Indian 1 (0.9) 1 (2.2) 0 Weight, kg, mean (SD) 66.2 (12.9) 64.4 (13.2) 67.9 (12.8) 0.266* TC, mmol/L, mean (SD) 5.72 (1.58) 5.60 (1.34) 5.79 (1.78) 0.200* LDL-C, mmol/L, mean (SD) 3.48 (1.29) 3.31 (1.09) 3.58 (1.42) 0.120* HDL-C, mmol/L, mean (SD) 1.39 (0.45) 1.43 (0.43) 1.40 (0.48) 0.657* SBP, mm Hg, mean (SD) 141 (24.5) 143 (23.5) 138 (24.9) 0.754* Diabetes, n (%) 55 (51.9) 22 (47.8) 33 (55.0) 0.464# Hypertension, n (%) 58 (54.7) 25 (54.3) 33 (57.6) 0.947# Smoking, n (%) 32 (30.2) 18 (39.1) 14 (23.3) 0.079# TC: total cholesterol; LDL-C: low density lipoprotein cholesterol; HDL-C: high density lipoprotein cholesterol; SBP: systolic blood pressure; SD: standard deviation * Student t-test, # Pearson’s chi-square test
Concordance with 2013 ACC/AHA Guideline on the treatment of blood cholesterol The overall rate of concordance with the 2013 ACC/AHA Guideline on the treatment of blood cholesterol was 43.4% as demonstrated in Table 2. The most commonly prescribed statin intensity in this study was moderate intensity (63.2%). The common indication of initiating statin treatment in patients of this cohort was clinical ASCVD (48.1%), followed by diabetes (26.4%), ASCVD risk of at least 5% (17.0%) and baseline LDL-C of ≥4.9 mmol/L (8.5%). Among patients who received guideline concordant statin therapy, 58.7% of them had history of clinical ASCVD, who required statin therapy for secondary prevention of ASCVD. However, patients with clinical ASCVD recorded the highest proportion (40.0%) among patients whom were not treated with guideline concordant statin therapy. Patients with baseline LDL-C of 4.9 mmol/L or higher, who had the second highest risk of developing ASCD, had the lowest rate of being treated with guideline suggested intensity statin therapy (4.3%). Although high intensity statin therapy was the most commonly suggested regimen (61.3%), a higher percentage of patient population of this study were started with moderate intensity statin 46 treatment (63.2%) instead. Moderate intensity statin therapy was the most frequent wrongly- prescribed treatment regimen (76.7%) when compared to high (3.3%) and low intensity statin regimen (20.0%) respectively. Of all the patients who received guideline discordant treatment, 73.3% of them received a lower statin intensity than what they were supposed to receive according to the guideline. When high intensity statin was prescribed, this regimen was used correctly in 92.6% of the occasions (Table 3). However, while moderate intensity statin therapy was the most commonly started treatment, only 31.3% of the patients (21 out of 67) were appropriately treated according to the guideline. Of patients who received moderate intensity statin therapy, half of them should have received high intensity statin treatment. Furthermore, of all the patients treated with low intensity statin, 75% should have received higher intensity therapy.
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Table 2: Characteristics of statin treatment among study population Guideline Guideline Characteristic, n (%) All concordant discordant P-value prescribing prescribing Overall 106 46 (43.4) 60 (56.6) Indication for statin therapy 0.215 Clinical ASCVD 51 (48.1) 27 (58.7) 24 (40.0) Baseline LDL-C ≥4.9 mmol/L 9 (8.5) 2 (4.30) 7 (11.7) Diabetes 28 (26.4) 11 (23.9) 17 (28.3) ASCVD risk ≥ 5% 18 (17.0) 6 (13.0) 12 (20.0) Guideline recommended statin intensity <0.001 High 65 (61.3) 25 (54.3) 40 (66.7) Moderate 26 (24.5) 21 (45.7) 5 (8.3) Statin not beneficial 15 (14.2) 0 15 (25.0) Prescribed statin intensity <0.001 High 27 (25.5) 25 (54.3) 2 (3.3) Moderate 67 (63.2) 21 (45.7) 46 (76.7) Low 12 (11.3) 0 12 (20.0) Reason for guideline discordance Dose lower than recommended - - 44 (73.3) Dose higher than recommended - - 16 (26.7) ASCVD: atherosclerotic cardiovascular diseases
Table 3: Concordance of prescribed statin therapy to the 2013 ACC/AHA guideline Prescribed statin Guideline suggested statin intensity therapy, n (%) intensity No benefit Moderate intensity High intensity Total High Intensity 1 (3.7%) 1 (3.7%) 25 (92.6) 27 (100) Moderate Intensity 12 (17.9%) 21 (31.3%) 34 (50.7) 67 (100) Low Intensity 3 (25.0%) 4 (33.3) 5 (41.7) 12 (100) Total 16 26 64 106
Therapeutic response of statin therapy Thirty patients did not have their fasting lipid tested after the initiation of statin therapy, so their treatment outcomes were not be assessed. In the remaining 76 patients, the overall success rate of achieving suggested percentage reduction in baseline LDL-C level was only 28.9% (Table 4). The 47 achievement of targeted LDL-C reduction in patients treated with guideline concordant statin therapy did not differ significantly from those who received guideline discordant statin therapy [odd ratio = 0.457 (95% confidence interval 0.165-1.259, p=0.129)]. Patient with clinical ASCVD had the lowest rate of achieving the recommended reduction in baseline LDL-C level (15.6%) when compared to the other 3 groups of patients. The highest success rate of achieving targeted percentage reduction in LDL-C concentration belonged to the group of patients with baseline LDL-C 4.9 mmol/L and higher (55.6%). There was a significantly higher percentage of patients started with low intensity statin therapy (75%) that achieved targeted reduction from baseline LDL-C level when compared to patient receiving high intensity (4.5%) and moderate intensity statin therapy (36%) (p=0.010). In contrast, the highest treatment failure rate of statin therapy was observed in group of patients whom were treated with high intensity statin therapy (95.5%). Nevertheless, a sub-analysis 47 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 found that there was a significantly higher percentage of patients with clinical ASCVD that were treated with high intensity statin therapy (77.8%) when compared to patients with baseline LDL-C ≥
4.9 mmol/L (7.4%), diabetes (11.1%) and ASCVD risk ≥ 5% (3.7%) respectively (p=0.020). Additionally, patients who had achieved targeted percentage reduction from baseline LDL-C were found to have higher baseline TC level (6.52 versus 5.65 mmol/L, p=0.033) and had higher baseline LDL-C level (4.23 versus 3.38 mmol/L, p=0.008). Among the 106 included patients, 17 (16.0%) patients did not come for follow up monitoring after being started with statin therapy. There was no statistically significant difference in the default rate across all four indication groups of patients (p=0.104). Similar finding was observed in patient being started with different intensities of statin treatment. There was no significant different in defaulted rate across these groups (p=0.059). There were no ACS events or adverse drug reactions documented on the patients’ clinical progress folder since patients were started on statin therapy. Only one patient reported to have at least three times increased in liver enzymes from baseline within three months period of starting statin therapy. The enzyme levels decreased to normal range after statin therapy was withheld.
Table 4: Treatment outcomes of statin therapy among study population Characteristic All Success, n (%) Fail, n (%) P-value Overall 76 22 (28.9) 54 (71.1) Indication for statin therapy, (%) 0.057 Clinical ASCVD 32 5 (15.6) 27 (84.4) Baseline LDL-C ≥4.9 mmol/L 9 5 (55.6) 4 (44.4) Diabetes 19 5 (26.3) 14 (73.7) ASCVD risk ≥5% 16 7 (43.8) 9 (56.2) Prescribed statin intensity, (%) 0.010 High 22 1 (4.5) 21 (95.5) Moderate 50 18 (36.0) 32 (64.0) Low 4 3 (75.0) 1 (25.0)
Discussion This observation study evaluated the overall concordance of statin prescribing at Hospital Kuala Krai with the 2013 ACC/AHA Guideline on the treatment of blood cholesterol. We found that the overall concordance rate to the guideline was 43.4% and this was lower compared to other published studies. A study conducted in the United States by Christina Ng et.al. reported an overall concordance to the guideline of 65.8%15. In addition, another study carried out in Saudi Arabia also reported relatively high 16 overall concordance rate of 72.4% . Almost all the patients with 10-years ASCVD risk ≥ 7.5% in the 48 US study received the correct intensity of statin therapy15, and about 80% of the patient with clinical ASCVD in the Saudi Arabia study were treated with the appropriate intensity of statin therapy16. Our study reported that the highest concordance rate was observed in patient with clinical ASCVD at only 52.9%. The overall concordance rate to the guideline needs to be improved, because when compared to other published studies, majority of our patients has higher systolic blood pressure, higher baseline LDL-C level and higher 10-years ASCVD risk15, 16. The study conducted in Saudi Arabia reported that their most common indication to start statin therapy was clinical ASCVD (54.7%)16. Similar finding was also observed in this study whereby almost half of the patients who received statin treatments were patients with clinical ASCVD (48.1%). However, in the United States, patients with diabetes mellitus were found to be the group that most frequently received statin therapy as primary prevention of ASCVD15. Although the majority of our
48 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 patients received statin for secondary prevention of ASCVD, but moderate-intensity statin was the most commonly prescribed intensity. This could indicate that our patients with clinical ASCVD, whom have the highest risk to develop fatal cardiovascular diseases, were possibly being under-treated. The utilisation of high-intensity statin therapy in our setting was appropriate with 92.6% concordance rate. Similar finding was observed in the US study which reported that the 92.5% of the total high intensity statin prescription abide by the guideline recommendation15. On the other hand, the study conducted in Saudi Arabia recorded a slightly lower high intensity statin concordance rate at 72.2%16. Although the usage of high intensity statin therapy in our setting was highly concordant to the guideline recommendation, but only 41.2% of patient with clinical ASCVD actually received high intensity statin treatment, which was significantly lower when compared to the Saudi Arabia study of 83.3% 16. In addition, moderate intensity statin therapy was found to be most frequently prescribed for our patients (63.2%) in which half of these patients should have received high-intensity statin therapy. A clinical trial showed that high intensity statin therapy with atorvastatin was able to reduce the risk of all-cause mortality after acute coronary syndromes (ACS) by 12%17. In addition, clinical trials such as ALLIANCE (Aggressive Lipid-Lowering Initiation Abates New Cardiac Events) and GREACE (GREek Atorvastatin and Coronary-heart-disease Evaluation) trials had highlighted the benefits of atorvastatin in reducing the risk of non-fatal myocardial infarction by 47-59%18. About 15% of total patients in this study were over treated with higher intensity statin, which was comparable to the Saudi Arabia’s study that recorded about 13.3%16. On the other hand, underutilisation of statin therapy were observed in more than one-third of the patients studied, which was similar with the US study15. The Arab study recorded a much lower underutilisation of statin therapy when compared to our study (21.0% versus 41.5%). This study was not able to identify the causes of inappropriate use of statin in our facility but other study had shown that the prescribing of statin seldom fully abide by the suggestions in the clinical practice guidelines19. A study conducted in Ireland that evaluated the influence of guideline on statin prescribing showed that although the overall prescribing rate of high intensity statin may increase in response to the guideline recommendations, it was still common to observe that physicians prescribed lower doses of statin therapy than those suggested in the clinical practice guideline20. Inaccurate estimation of ASCVD risk was found to be another factor contributed to non-concordance in the prescribing of statin treatment21. Our study found that around seventy percent of the patients failed to achieve the targeted treatment goal after three months of statin therapy and only 15.6% of patients with clinical ASCVD were able to achieve targeted percentage of LDL-C reduction. Four hallmark trials, which studied the benefits of the high-intensity statin therapy against moderate intensity statin therapy in patients with post-acute coronary syndrome or coronary artery disease, also showed that, patients were not able to achieve at least 50% reduction in serum LDL-C concentration at the end of the trials 22-25. However, in these trials, average LDL-C concentration was less than 1.8mmol/L at the end of the studies. The ACC/AHA 2013 guideline did not recommend the LDL-C treatment target as there was insufficient evidence to support such a recommendation13. Even though patient had been treated with guideline- 49 concordant statin therapy, the percentage reduction in the LDL-C concentration can be affected by other factors such as patients’ compliance to medication and inter-patient metabolic variability in the response to statin treatment. These factors were not assessed in this study. This study had several limitations. First of all, this is a retrospective study, hence there were many instances that documentation was incomplete or patients’ data was missing. In addition to statin therapy, the guideline also suggested concordance to diet modification, healthy lifestyle and medication compliance, which were not included in this study for analysis. Additionally, the shared- decision making and clinician-risk discussion in starting statin therapy could not be captured in this study, thus its effect on the concordance rate was not able to be determined. Finally, this study was done in a single facility with limited sample size, thus the results could not be generalised and provide a true indication on the overall concordance rate at the national level. 49 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018
Conclusion In conclusion, only about 40% of our patients received appropriate intensity statin therapy as per guideline recommendation, which needs to be improved. Our study provided an overview on the utilisation of statin therapy in our facility. We hope that, with the introduction of the latest Malaysia clinical practice guideline on the management of hyperlipidaemia 2017, the overall guideline- concordant statin prescribing rate can be improved and the prescribing of statin therapy can be optimised.
Acknowledgement We would like to thank the Director General of Health Malaysia for his permission to publish this article.
Conflict of Interest Statement No external funding was received and the authors declared no conflict of interest.
References 1. WHO. Noncommunicable diseases country profiles 2014. 2014. 2. WHO. Country Statistics and Global Health Estimates. 2015. 3. Dans A, Ng N, Varghese C, Tai ES, Firestone R, Bonita R. The rise of chronic non-communicable diseases in southeast Asia: time for action. The Lancet. 2011;377(9766):680-9. 4. Abd Kadir Abu Bakar AAAG, Abu Bakar Rahman, Ahmad Ali, Zainuddin ANJ, Arunah Chandran, Asmah Razali, Azli Baharudin,, Azriman Rosman BMN, Chan Ying Ying, Chandrika Jeevenathan,, Cheong Siew Man CE, Faizah Paiwai, Fatanah Ismail, Fatimah, Othman FIM, Gunenthira Rao a/l Subbarao, Hamizatul Akmal, Abd Hamid HI, Idayu Badilla Idris, Jane Ling Miaw Yn, Jemsee Onggi,, et al. National Health and Morbidity Survey 2015, Volume II: Non-communicable Diseases, Risk Factors & Other Health Problems. Institute of Public Health, National Institute of Health, Ministry of Health Malaysia 2015;2. 5. Jousilahti P, Laatikainen T, Peltonen M, Borodulin K, Männistö S, Jula A, et al. Primary prevention and risk factor reduction in coronary heart disease mortality among working aged men and women in eastern Finland over 40 years: population based observational study. bmj. 2016;352:i721. 6. MOH. Management of Dyslipidemia 5th ed. Malaysia: MOH; 2017. 7. Calvin JE, Shanbhag S, Avery E, Kane J, Richardson D, Powell L. Adherence to evidence‐based guidelines for heart failure in physicians and their patients: Lessons from the Heart Failure Adherence Retention Trial (HART). Congestive heart failure. 2012;18(2):73-8. 8. Grol R. Successes and failures in the implementation of evidence-based guidelines for clinical practice. Medical care. 2001;39(8):II-46-II-54. 50 9. Sharif R, Cuevas CR, Wang Y, Arora M, Sharma G. Guideline adherence in management of stable chronic obstructive pulmonary disease. Respiratory medicine. 2013;107(7):1046-52. 10. Teeling M, Bennett K, Feely J. The influence of guidelines on the use of statins: analysis of prescribing trends 1998–2002. British journal of clinical pharmacology. 2005;59(2):227-32. 11. Alburikan KA, Asiri RM, Alhammad AM, Abuelizz AA, Bawazeer GA, Aljawadi MH. Utilization and adherence to guideline-recommended lipid-lowering therapy at an academic medical center. Annals of Saudi medicine. 2017;37(4):276. 12. Ng C, Chung P, Toderika Y, Cheng-Lai A. Evaluation of adherence to current guidelines for treatment of hyperlipidemia in adults in an outpatient setting. American Journal of Health-System Pharmacy. 2016; 73(23 Supplement 6): S133-S40.
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13. Stone NJ, Robinson J, Lichtenstein AH, Merz CNB, Blum CB, Eckel RH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013. 14. Zupec JF, Marrs JC, Saseen JJ. Evaluation of Statin Prescribing for Secondary Prevention in Primary Care Following New Guideline Recommendations. The Annals of pharmacotherapy. 2016;50(1):17-21. 15. Ng C, Chung P, Toderika Y, Cheng-Lai A. Evaluation of adherence to current guidelines for treatment of hyperlipidemia in adults in an outpatient setting. American journal of health-system pharmacy. 2016; 73(23 Supplement 6): S133-s40. 16. Alburikan KA, Asiri RM, Alhammad AM, Abuelizz AA, Bawazeer GA, Aljawadi MH. Utilization and adherence to guideline-recommended lipid-lowering therapy at an academic medical center. Annals of Saudi medicine. 2017;37(4):276-81. 17. Foody JM, Joyce AT, Rudolph AE, Liu LZ, Benner JS. Cardiovascular outcomes among patients newly initiating atorvastatin or simvastatin therapy: a large database analysis of managed care plans in the United States. Clinical therapeutics. 2008;30(1):195-205. 18. Arca M, Gaspardone A. Atorvastatin efficacy in the primary and secondary prevention of cardiovascular events. Drugs. 2007;67 Suppl 1:29-42. 19. Langner NR, Hasselback PD, Dunkley GC, Corber SJ. Attitudes and practices of primary care physicians in the management of elevated serum cholesterol levels. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 1989;141(1):33-8. 20. Teeling M, Bennett K, Feely J. The influence of guidelines on the use of statins: analysis of prescribing trends 1998-2002. British journal of clinical pharmacology. 2005;59(2):227-32. 21. Pignone M, Phillips CJ, Elasy TA, Fernandez A. Physicians' ability to predict the risk of coronary heart disease. BMC Health Services Research. 2003;3:13-. 22. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. The New England journal of medicine. 2004;350(15):1495-504. 23. de Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox KA, White HD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. Jama. 2004;292(11):1307-16. 24. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. The New England journal of medicine. 2005;352(14):1425-35. 25. Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. Jama. 2005;294(19):2437-45. 51
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Retrospective Review of Postnatal Growth Rate of Premature Infants Receiving Early
Parenteral Nutrition in a Malaysian Tertiary Hospital Neonatal Intensive Care Unit
Loo Jing Hean1, Limata @ Monalita Binti Othman1
1 Sultan Abdul Halim Hospital, Ministry of Health Malaysia
Abstract
Introduction: Parenteral nutrition (PN) caters for the needs of very low birth weight premature neonates whom the establishment of full enteral nutrition is likely to be delayed. Previous studies demonstrated that early aggressive PN improves neonatal growth parameters. The nutritional goal in premature infants is to achieve postnatal growth rate that is similar to intrauterine foetal growth. Objective: The objectives of this study were (1) to evaluate the postnatal weight gain rate of low birth weight preterm infants who received early PN, (2) to evaluate the association between co-morbidities in premature infants with weight gain and the correlation between the initiation time and duration of PN with weight gain. Methods: This was a single centre, retrospective review of premature infants with birth weight less than 1,400 gram receiving PN from January to December 2013. Data were collected from the subjects' medical records. Postnatal weight gain rate from day 7 to day 28 of life was calculated. Results: The overall median weight gain rate at day 28 was 14.15 gram/kg/day (IQR 6.44), which was slightly below the recommended growth rate of 15 gram/kg/day. The weight gain in neonates with patent ductus arteriosus were significantly lower than their counterparts (median 9.10 gram/kg/day versus 15.03 gram/kg/day, p<0.01). The correlation between both initiation time of PN (rs = -0.141, p =
0.381) and duration of PN (rs = -0.081, p = 0.613) with weight gain were weak and not statistically significant. Conclusion: Early PN is a vital nutritional support for neonates to achieve targeted weight gain, overcoming the initial weight drop postnatally, when enteral feeding is not feasible. Nevertheless, the majority of our cohort did not achieve the recommended growth rate despite early initiation of PN. Presence of one or more co-morbidities influences the neonatal weight gain outcome.
Keywords: parenteral nutrition; weight gain; premature neonates
NMRR ID: NMRR-15-964-26135
Corresponding author: 52 Loo Jing Hean Pharmacy Department, Sultan Abdul Halim Hospital, Jalan Lencongan Timur, Bandar Aman Jaya, 08000 Sungai Petani, Kedah Email: [email protected]
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Introduction Poor postnatal growth is often observed in preterm infants1. Several studies have revealed that preterm infants are often being discharged at a considerably lower percentile of weight, head circumference and length2-3. Although the reason for this poor growth can be multifactorial, one of the essential factors is that these infants receive inadequate nutrients at the recommended target, especially early in life1. It is very challenging to provide sufficient nutritional intake in preterm infants as they are often unable to tolerate the volume of oral feeds that provide adequate daily requirements for their growth within the first week or two of life. To address this problem, one of the nutritional approaches that was recently advocated was early "aggressive" parenteral nutrition initiation after birth1,4. Parenteral nutrition (PN) is the intravenous infusion of all nutrients necessary for metabolic requirement and growth. PN are able to cater for the needs of very low birth weight premature neonates whom the establishment of full enteral nutrition is likely to be delayed. Premature neonates can tolerate PN as early as their first day of postnatal life. Moyses and colleagues1 have conducted a systematic review and meta-analysis in 2013 to investigate the effect of early PN on the growth outcome in preterm infants and concluded that early PN improves weight gain with no increase in morbidity or mortality. The ultimate nutritional goal in premature infants is to achieve postnatal growth rate that is similar to intrauterine growth5. Foetus grows at a minimum rate of 15g/kg/day during mid-trimester and reduces to 10g/kg/day at term. Uhing and Das6 had also suggested that the optimal postnatal growth rate for premature infants is to mimic the intrauterine growth velocity which is approximately 16g/kg/day for 23 and 37 weeks’ gestation. However, postnatal weight gain in preterm infants is often not attained due to the increased energy requirement associated with under-nutrition, severe illnesses and other co-morbidities7-8. Current standard for postnatal nutrition in preterm infants is the one that duplicates normal intrauterine foetal growth rates. In our hospital, the neonatal intensive care unit (NICU) uses the Guidelines of Paediatric Parenteral Nutrition of The European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and European Society for Clinical Nutrition and Metabolism (ESPEN) as the standard in prescribing PN for preterm infants. Nevertheless, the outcome of local premature infants receiving PN according to these guidelines has not been reported. Therefore, this study aimed to provide some insight into the outcome of premature infant population who receive early PN in the local setting. The primary objective of this study was to measure the postnatal weight gain rate of premature infants receiving early PN support within the first 48 hours of life in the NICU. Besides that, this study also evaluated the association between common co-morbidities in premature infants with weight gain and the correlation between the initiation time and duration of PN with weight gain.
Methods 53 Study Participants This was a single-centre, retrospective observational review of postnatal growth rate of premature infants receiving early PN in a Malaysian tertiary hospital NICU from 1 January 2013 to 31 December 2013. Inclusion criteria were neonates with very low birth weight of less than 1,400 grams, who received PN that was initiated within 48 hours of life, for a minimum duration of five days. We excluded premature infants with major congenital anomalies, died before day 28 of life, and those who did not have their weight measured on day 7, day 28 and upon discharge.
Data Collection A standard data collection form was designed to extract information from patient's medical records. Demographic data including birth weight and gestational age at birth were recorded. Other co- 53 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 morbidities during hospitalisation including small for gestational age at birth, patent ductus arteriosus, intraventricular haemorrhage (all grades), necrotising enterocolitis and late-onset sepsis or infection were also recorded. Detailed nutritional parameter including total calories and amount of macronutrients provided by PN during the first week of life were documented as well. Initiation time and duration of PN were collected. Subjects' body weight measured at day 7,day 28 and upon discharge using the same electronic digital scales accurate to 10 grams were documented. Time to regain birth weight was also obtained.
Nutritional Management According to the NICU policy, all new-born infants born with birth weight less than 1,400 grams are initiated with PN as soon as possible, preferably within the first day of life. A standard premixed PN solution bag containing 10% dextrose and 3% amino acid is administrated until the individualised PN solution is available. Fluid intake is restricted to 60 ml/kg/day on day 1, and then advanced by 10-20 ml/kg/day to 150 ml/kg/day at day 7 of life. Enteral feeding is initiated as trophic feeding (<20 ml/kg/day) with breast milk or preterm formula if breast milk is unavailable. When the enteral feeding increases, the amount of PN solution infused is reduced accordingly. PN supplementation is discontinued when enteral feeding achieves 120 ml/kg/day.
Growth Outcomes The primary outcome of this study was postnatal weight gain rate. Due to the inevitable weight loss in the first week of life and the possibility that the impact of early nutrition on body weight would not be seen until after day 7, weight gain was calculated from day 7 to day 285. The formula for weight gain rate was: (wt - wt ) / wt weight gain rate (gram/kg/day) = 1000 x 28 7 7 28 - 7
wt 28 - weight on day 28 (kg) wt 7 - weight on day 7 (kg)
Time to regain birth weight was also analysed. Our aims of postnatal growth rate and time to regain birth weight were 15 gram/kg/day and 14 days respectively.
Statistical Analysis We performed all analysis using SPSS software version 16.0. The percentage of infants achieving optimum weight gain of at least 15gram/kg/day on day 28 and the percentage of infants that regained birth weight by day 14 were calculated. Other statistical applications included Man-Whitney U Test was used to analyse the association between common co-morbidities in preterm infants with weight gain and Spearman correlation test was used for the correlation of initiation time and duration of PN 54 with weight gain.
Ethics Statement This study was registered with the National Medical Research Register (NMRR) (NMRR-15-964- 26135) and approved by the Medical Research and Ethics Committee (MREC).
Results A total of 41 preterm infants were included in our study. Demographic and co-morbidity data of the study population were demonstrated in Table 1 and Table 2. More than a quarter of our cohort (26.8%, n=11) were born small for gestational age. The overall median weight gain at day 28 was 14.15 gram/kg/day (interquartile range (IQR) 6.44), which was slightly below our target of 15 gram/kg/day. Of
54 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 the total neonates included for the review, 97.6% (n=40) experienced weight drop to lower than birth weight on day 7 of life. Then, 43.9% (n=18) achieved targeted weight gain of at least 15 g/kg/day while 63.4% (n=26) of the subjects regained their birth weight by day 14. The median duration to regain birth weight was 14 days (IQR 8.00). As high as 87.8% (n=36) of them had extrauterine growth failure which was defined as body weight below the 10th percentile. Neonates with comorbidities had poorer weight gain. Weight gain in neonates with patent ductus arteriosus were significantly lower compared to the others (median 9.10 g/kg/day versus 15.03 g/kg/day, p <0.01). Otherwise, the impact of other co-morbidities (small for gestational age at birth, intraventricular haemorrhage, necrotising enterocolitis and late-onset sepsis or infection) on postnatal weight gain is not statistically significant (Table 3). With regards to the correlation of initiation time and duration of PN with weight gain, there was a poor negative correlation between initiation time of PN and weight gain at day 28, and it was not statistically significant (rs = -0.141, p = 0.381) (Figure 1). Similarly, the correlation between duration of PN and weight gain at day 28 was also poor and statistically insignificant (rs = -0.081, p = 0.613) (Figure 2).
Table 1: Demographic characteristics of the study population (N=41) Characteristics n (%) Gender Male 22 (53.7) Female 19 (46.3) Ethnicity Malay 38 (92.7) Chinese 1 (2.4) Indian 1 (2.4) Others 1 (2.4) Gestational age (weeks) ˂ 28 14 (34.1) 28 – 32 26 (63.4) > 32 1 (2.4) Birth weight (grams) 601 – 800 6 (14.6) 801 – 1,000 14 (34.1) 1,001 – 1,200 19 (46.3) 1,201 – 1,400 2 (4.9)
Table 2: Co-morbidities of the study population (N=41) 55 Co-morbidity n Small for gestational age at birth 11 Intraventricular haemorrhage 12 Necrotising enterocolitis 3 Late onset sepsis / infection 8 Patent ductus arteriosus 10
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Table 3: Association between common co-morbidities in preterm infants with growth rate at day 28 (N=41)
Growth rate, g/kg/day, Co-morbidity n P-value* median (IQR) Small for gestational age at birth 0.508 Yes 11 13.88 (6.40) No 30 14.50 (7.62) Intraventricular haemorrhage 0.352 Yes 12 13.97 (8.94) No 29 14.15 (6.21) Necrotising enterocolitis 0.617 Yes 3 12.27 (8.82) No 38 14.50 (5.99) Late onset sepsis / infection 0.402 Yes 8 12.50 (8.82) No 33 14.84 (5.82) Patent ductus arteriosus 0.009 Yes 10 9.10 (9.82) No 31 15.03 (5.98) * Mann-Whitney U test
Figure 1: Scatter plot of initiation time of PN and weight gain at day 28
r = -0.141
56
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Figure 2: Scatter plot of duration of PN and weight gain at day 28
r = -0.081
Discussion In the early neonatal period of premature infant, PN replaces the role of placenta in ensuring continuous provision of nutrient to the growing neonates9. The current standard for postnatal nutrition in preterm infants aims to achieve normal intrauterine foetal growth rates. With regards to the total daily energy provision, the American Academy of Pediatrics (AAP) Committee on Nutrition advocated that energy intake of 50 kcal/kg/day is necessary for basal metabolic function10. The postnatal growth is proportional to the provision of energy beyond 50 kcal/kg/day, in which 5 kcal/kg/day is required for every 15gram/kg/day of weight gain. Energy intake can also influence the nitrogen balance and protein accretion is likely to improve with a higher calorie intake11. Premature infants require a minimum energy supply of 50 to 60 kcal/kg/day, but 110 to 130 kcal/kg/day is needed to support optimal protein accretion and growth4,7,11. Lipid provides additional energy and enables the preterm infants to achieve the target energy requirement faster12. Lipid was also administrated to our patients at an initial dose of one gram/kg/day together with glucose and amino acid on the first day of life, which was then increased by one gram/kg/day to the target of three gram/kg/day. Despite the early 57 provision of lipid, our study population only received approximately 35 kcal/kg/day of energy on day 1 with subsequent advancement of 10-15 kcal/kg/day, which was still below the recommended minimum energy intake. This could explain why only 44% (n=18) of our subjects had achieved the targeted weight gain of 15gram/kg/day. Many literatures agreed that early protein intake may lead to better growth outcomes11. Olsen et al.13 proposed that weight gain in premature infants could be raised by 4.1 gram/kg/day with every additional one gram/kg/day of protein. In premature infants, at least one gram/kg/day of amino acid is needed for net protein balance close to zero, while protein accretion will require three gram/kg/day of amino acid11. Administration of glucose alone without amino acid can result in 1-2% loss of the total endogenous body protein in extremely low birth weight infants (birth weight < 1,000 gram)11. In view of that, provision of amino acid should be started early within 24 hours of birth at 1.5 to 3.0 gram/kg/day
57 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 with increment to a target of 3.5 to 4.0 gram/kg/day5. Recently, some researchers advocated a higher starting dose of amino acid at 3 gram/kg/day which approximates in utero amino acid flux in animal studies, in the hope of reducing the rate of extrauterine growth failure14. While the observational study by Maggio et al.15 has demonstrated better growth outcome in infants receiving higher dose of amino acid supplementation, other controlled trials9,14,16 have reported that high dose of amino acid did not show benefit on the growth parameters of premature infants. Our policy of amino acid delivery in PN for preterm infants is 3 gram/kg/day on day 1, and then increased to 4 gram/kg/day on day 2 and onwards. However, due to fluid restriction, majority of our cohort has only received 1.5 gram/kg/day of amino acid on day 1 of life and advanced daily at the rate of 1 gram/kg/day to a target dose of 4 gram/kg/day on day 3 or 4, which fell below the recommendation of high dose amino acid. In previous published studies, postnatal growth rate has been calculated in many different ways using varying starting points (birth weight, nadir, time regained birth weight) and time interval. Lack of standardisation makes the comparison of growth rate between studies difficult. We chose the interval from day 7 to day 28 in our calculation rather than from birth to day 28 with the assumption that the adequacy of the nutritional practice would be better reflected by the weight gain after day 75. Martin et al.5 used the same weight gain calculation for their subjects. Our cohort achieved median weight gain of 14.15 gram/kg/day at day 28, which was lower than the median weight gain of 18.3 gram/kg/day reported in the study by Martin et al5. Although these patients received early PN within the first 48 hours of life, the nutritional practice in our centre was not able to meet some of recommendations with regards to total calorie and amino acid intake on the first few days of life. Achieving minimum energy intake of 50-60 kcal/kg/day during the first few days of life can be challenging due to fluid restriction competing against provision of adequate calorie. The high incidence of extrauterine growth failure at the time of discharge was observed from our cohort and this is consistent with the findings of many other studies5,17. Compared to the healthy foetus in utero, premature infants do not have nutritional and growth factor supply from maternal placenta despite their higher energy requirement. Furthermore, weight loss as much as 15% during the first week of life is not accounted for in the intrauterine growth rate. Therefore, postnatal growth failure may be unavoidable as it may not be possible to imitate the intrauterine growth rate, even with the current recommended target postnatal weight gain of 15 gram/kg/day5. Previous studies by Ehrenkranz18 have proposed that premature infants with one or more co- morbidities have poorer growth rate. This is similar to the finding of our study. The energy requirement for those critically ill preterm infants may be even higher than the healthy premature infants5. In addition, these severely ill infants sometimes need continuous infusion of other medications such as sedative and inotrope, hence requiring reduction in the infusion rate of PN9. In infants with patent ductus arteriosus where one of the conservative management is fluid restriction, achieving adequate calorie intake with the restricted total fluid volume can be very challenging. Hence, it is not surprising that infants with patent ductus arteriosus had a significantly poorer weight gain than their counterparts. The main limitation of our retrospective study was the use of weight gain as sole indicator in 58 evaluating nutritional adequacy. Growth outcome of our cohort should include other anthropometric measures such as length and head circumstance5. Although the height and head circumference was measured weekly in our unit, these data were not utilised for this study as they were not measured by the same operator and hence are subject to bias. Besides that, our subject's body weight was not measured daily during the first postnatal week of life. As the result, the maximum weight loss, which could be another useful growth parameter as described in many other studies, could not be determined in our studies. Thirdly, the types and total calories of enteral feeding from the day of full feeding to day 28 could be a confounding factor affecting our subjects' postnatal weight gain at day 28 of life and upon discharge. This aspect of enteral feeding was not investigated in our study as the detailed data could not be obtained due to its retrospective nature.
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Conclusion Early PN is a vital nutritional support for premature neonates to achieve targeted weight gain and to overcome the initial postnatal weight drop when enteral feeding is not feasible. The majority of our cohort did not achieve the recommended growth rate of 15 gram/kg/day weight gain despite early initiation of PN. The presence of one or more co-morbidities influenced the neonatal weight gain outcome. The major challenge in providing adequate nutritional support during early neonatal period in premature infants was the need for fluid restriction which could limit nutrition delivery.
Acknowledgement We would like to thank the Director General of Health Malaysia for his permission to publish this article. We gratefully acknowledge the contribution of our consultant in the NICU and Clinical Research Centre Kedah.
Conflict of Interest Statement No external funding was received and the authors declared no conflict of interest.
Reference 1. Moyses H; Johnson M; Leaf A; Cornelius V. Early parenteral nutrition and growth outcomes in preterm infants: a systematic review and meta-analysis. American Journal of Clinical Nutrition. 2013, 97(4), 816-826. 2. Ehrenkranz R. Early, Aggressive Nutritional Management for Very Low Birth Weight Infants: What Is the Evidence?. Seminars in Perinatology. 2007, 31(2), 48-55. 3. Wood N. The EPICure study: growth and associated problems in children born at 25 weeks of gestational age or less. Archives of Disease in Childhood - Fetal and Neonatal Edition. 2003,88(6), 492F-500. 4. Koletzko B; Goulet O; Hunt J; Krohn K; Shamir R. 1. Guidelines on Paediatric Parenteral Nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), Supported by the European Society of Paediatric Research (ESPR). Journal of Pediatric Gastroenterology and Nutrition. 2005, 41(Supplement 2):S1-S4. 5. Martin C; Brown Y; Ehrenkranz R et al. Nutritional Practices and Growth Velocity in the First Month of Life in Extremely Premature Infants. PEDIATRICS. 2009, 124(2), 649-657. 6. Uhing M; Das U. Optimizing Growth in the Preterm Infant. Clinics in Perinatology. 2009, 36(1), 165-176. 7. Velaphi S. Nutritional requirements and parenteral nutrition in preterm infants. S Afr J Clin Nutr. 2011, 24(3), S27-S31. 8. Hay W. Assessing the effect of disease on nutrition of the preterm infant. Clinical Biochemistry. 1996, 29(5), 399-417. 59 9. Yang S; Lee B; Park H et al. Effect of High vs Standard Early Parenteral Amino Acid Supplementation on the Growth Outcomes in Very Low Birth Weight Infants. Journal of Parenteral and Enteral Nutrition. 2012, 37(3), 327-334. 10. American Academy of Pediatrics, Committee on Nutrition. Nutritional needs of low-birth-weight infants. Pediatrics 1977, 60, 519-530. 11. Denne S; Poindexter B. Evidence Supporting Early Nutritional Support with Parenteral Amino Acid Infusion. Seminars in Perinatology. 2007, 31(2), 56-60. 12. Herrmann K; Herrmann K. Early Parenteral Nutrition and Successful Postnatal Growth of Premature Infants. Nutrition in Clinical Practice. 2010, 25(1), 69-75. 13. Olsen I; Richardson D; Schmid C; Ausman L; Dwyer J. Intersite Differences in Weight Growth Velocity of Extremely Premature Infants. PEDIATRICS. 2002, 110(6),1125-1132. 59 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018
14. Clark R; Chace D; Spitzer A. Effects of Two Different Doses of Amino Acid Supplementation on Growth and Blood Amino Acid Levels in Premature Neonates Admitted to the Neonatal Intensive Care Unit: A Randomized, Controlled Trial. PEDIATRICS. 2007, 120(6), 1286-1296. 15. Maggio L; Cota F; Gallini F; Lauriola V; Zecca C; Romagnoli C. Effects of High versus Standard Early Protein Intake on Growth of Extremely Low Birth Weight Infants. Journal of Pediatric Gastroenterology and Nutrition. 2007, 44(1), 124-129. 16. Burattini I; Bellagamba M; Spagnoli C et al. Targeting 2.5 versus 4 g/kg/day of Amino Acids for Extremely Low Birth Weight Infants: A Randomized Clinical Trial. The Journal of Pediatrics. 2013, 163(5), 1278-1282.e1. 17. Clark R; Wagner C; Merritt R et al. Nutrition in the Neonatal Intensive Care Unit: How Do We Reduce the Incidence of Extrauterine Growth Restriction?. J Perinatol. 2003, 23(4), 337-344. 18. Ehrenkranz R. Early nutritional support and outcomes in ELBW infants. Early Human Development. 2010, 86(1), 21-25.
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60 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018
Knowledge and Attitude on Safe Handling of Cytotoxic Agents among Healthcare Staff
in Tengku Ampuan Rahimah Hospital (HTAR), Klang
Lee Jian Lynn1, Tai Chu Hong1, Lim Soon Seng1, Keng Zhi Hong1, Nur Syuhada Zainudin1, Yeo Wei Yan1, Lee Sheah Lin1, Khairul Azrul Abdul Rahman1
1 Tengku Ampuan Rahimah Hospital, Ministry of Health Malaysia
Abstract
Introduction: Cytotoxic agents are known to be teratogenic and mutagenic. Inappropriate handling of these agents can lead to occupational hazards among the healthcare staff especially nurses who are mainly involved in the handling of cytotoxic agents. Objective: To assess the nurses’ knowledge and attitude on the safe handling of cytotoxic agents and to identify possible factors that influence the knowledge of safe handling of cytotoxic agents in HTAR, Klang. Methods: A cross-sectional survey using a validated self-administered questionnaire was carried out. The questionnaires were distributed to all the 106 staff nurses from six wards that handle cytotoxic agents in HTAR. Ethics approval was obtained prior to the commencement of data collection. Results: Data collected from 96 staff nurses were included in the analysis. The mean age of the nurses was 27.75 (SD 4.37) years old. The duration of nursing and cytotoxic drug handling experience were 4.21 (SD 3.77) and 2.76 (SD 2.24) years respectively. The mean knowledge score on safe handling of cytotoxic agents was 58.46 (SD 12.88). Cytotoxic drug handling in most nurses were taught by senior staff (85.4%) and only 6.3% of nurses received formal post-registration education on chemotherapy. Our study found no significant correlation between the duration of nursing experience (r=0.081, p=0.433) and cytotoxic drug handling experience (r=0.057, p=0.581) with the knowledge score. Conclusion: The knowledge and attitude on cytotoxic drug handling among the nurses in HTAR were just slightly above average. Only a handful of the nurses received formal post-registration education on chemotherapy. The knowledge on cytotoxic safe handling was not correlated with the duration of nursing and cytotoxic drug handling experience. Continuous education and structured trainings are required to improve the knowledge and awareness on the safe handling of cytotoxic agents.
Keywords: cytotoxic agents, nurses, occupational exposure
NMRR ID: NMRR-17-2553-37801 61
Corresponding author: Lee Jian Lynn Pharmacy Department Tengku Ampuan Rahimah Hospital, Jalan Langat, 41200 Klang, Selangor Email: [email protected]
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Introduction The term cytotoxic is used to describe any agent that may be hazardous to the cells in any way. Cytotoxic agents are primarily intended for the treatment of cancer1. In 2012, worldwide statistics showed that there were a total of 32.6 million people living with cancer with 14.1 million of new cases and 8.2 million cancer deaths (within 5 years of diagnosis)2. In Malaysia, the incidence of newly diagnosed cancer was 37,426 cases in 20122. In Tengku Ampuan Rahimah Hospital (HTAR), intravenous cytotoxic drugs is administered in the Chemotherapy Day Care Unit, Obstetrics And Gynaecology, Surgical (2 wards), Haematology and Nephrology wards. Common indications include blood cancer, solid cancer, nephrology (lupus nephritis), rheumatology (systemic lupus erythematosus and rheumatoid arthritis) and ectopic pregnancy. Injectable cytotoxic drugs are prepared by the Pharmacy Department’s Cytotoxic Drug Reconstitution (CDR) Unit in the cytotoxic clean room and then supplied to the respective wards in the hospital. Oral cytotoxic drugs are kept in CDR Unit and outpatient pharmacy and directly dispensed to the patients. With the rise in the number of cancer patients, the usage of cytotoxic agents increases as well. In the inpatient care settings, nurses are one of the main groups of healthcare professionals that are exposed to these drugs as they are the ones who handle and administer the products to the patients. Exposed nurses risk the same adverse effects as patients with no therapeutic benefits. Possible chronic effects include cancer, fertility problems, long term genetic changes in off springs, abortion and abnormalities in the fetus3. Therefore, the knowledge, awareness and adherence of nurses regarding the safe handling of cytotoxic agents are essential to minimise occupational exposure. To date, several studies have been conducted to assess the attitude and knowledge of safe handling of cytotoxic agents among nurses4-7. HTAR being one of the state hospitals, and the second busiest hospital in Malaysia, was lacking such data. Hence, this cross-sectional survey study is important to determine the attitude and knowledge in safe handling of cytotoxic agents among the nurses in this hospital and could serve as a benchmark for future interventions. The objectives of this study were 1) to assess the current knowledge and attitude in the safe handling of cytotoxic agents among the nurses, and 2) to identify possible factors that influence the knowledge of safe handling of cytotoxic agents in HTAR.
Methods The questionnaire was adapted from a previously validated survey developed by Keat et al.5. The self- administered questionnaires were distributed to all staff nurses in the six wards that handle cytotoxic agents in HTAR during the study period from December 2017 to January 2018. The completed questionnaires were then returned to the study team. All staff nurses who were involved in any stage of cytotoxic agent handling such as collection, transportation, reconstitution, dilution, dispensing and administration to patients, storage, disposal, and spillage management of cytotoxic agents during the study period were included. This research 62 was approved by the Medical Research and Ethical Committee (MREC) and was granted with National Medical Research Registry (NMRR) identity number of NMRR-17-2553-37801. Both descriptive and analytical statistics were used. Nurse characteristics such as gender and marriage were presented in frequency (n) and percentage (%). Continuous data such as age, nursing experience and cytotoxic drug handling experience were expressed as mean and standard deviation (SD). All data were tabulated in table forms. Spearman correlation test was used to evaluate the association between the mean knowledge score and possible factors which may influence the score, which are nursing experience and cytotoxic drug handling experience. A p-value less than 0.05 was considered as statistically significant. Data were analysed using the Statistical Package for Social Sciences (SPSS) version 23.0.
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Results A total of 106 staff nurses from six different wards that handles cytotoxic agents participated in the survey. Howe ver, only 96 survey forms were analysed as ten were excluded due to incomplete forms. The demographic characteristics of respondents were shown in Table 1. The mean age of the nurses was 27.75 (SD 3.47) years old. Years of nursing experience and cytotoxic drug handling experience were 4.21 (SD 3.77) and 2.76 (SD 2.24) years respectively. The findings of nurses’ knowledge were as tabulated in Table 2. The mean knowledge score on safe handling of cytotoxic agents was 58.46 (SD 12.88). The data was then further analysed according to the wards of the respondents (Table 3). Among all the wards involved in this study, Chemotherapy Day Care Unit, with only three staff nurses, scored the highest. Figure 1 showed the chemotherapy training methods that the nurses received. Cytotoxic drug handling in the majority of nurses were taught by senior staff (85.4%) and the percentage of nurses who received formal post- registration education on chemotherapy was only 6.3%. Figure 2 showed the attitude of nurses towards safety related issues of cytotoxic drug handling. Most of the nurses (60.4%) felt confident to handle cytotoxic drugs safely. Some of them (28.1%) believed that complete personal protective equipment (PPE) usage were unnecessary, while some of the nurses (30.2%) were worried about long-term side effects of occupational exposure. Only a small percentage (7.3%) of nurses were able to tolerate a certain level of improper practice when they are busy, but around quarter of them (28.1%) were able to tolerate a certain level of improper practice among their peers. Further analysis with Spearman correlation showed that there was no significant correlation between the duration of nursing experience (r=0.081, p=0.433) and cytotoxic drug handling experience (r=0.057, p=0.581) with the nurses’ knowledge scores on cytotoxic safe handling.
Table 1: Demographics of respondents in HTAR (N = 96) Characteristics n (%) / mean (SD) Gender, n (%) Male 3 (3.1) Female 93 (96.9) Age, mean (SD) 27.75 (3.47) Marital status, n (%) Married 60 (62.5) Unmarried 36 (37.5) Nursing experience, mean (SD) 4.21 (3.77) Cytotoxic drug handling experience, mean (SD) 2.76 (2.24) 63
Table 2: Mean scores of staff nurses’ knowledge on general and four important areas of cytotoxic drug handling (N = 96) Topic of concern Score, mean (SD) Total score Hazardous effect 13.82 (4.28) 25 Chemotherapy exposure 9.58 (3.26) 15 Use of PPE 7.84 (2.45) 15 Safe handling measures 27.21 (7.43) 45 Overall 58.46 (12.88) 100
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Table 3: Mean scores of staff nurses’ knowledge on cytotoxic drug handling according to ward Ward Score, mean (SD) Number of respondents
Chemotherapy Day care 75.83 (5.2) 3 Haematology 65.63 (6.65) 24 Surgical 1 61.2 (6.46) 29 Obstetrics & Gynaecology 59.0 (9.34) 15 Surgical 2 54.33 (12.48) 15 Nephrology 33.5 (11.97) 10 Total 58.46 (12.88) 96
Figure 1: Methods of learning cytotoxic drug handling
90 85.4 80 70
60 49.0 50 38.5 40 30 Percentage (%) Percentage 20.8 20 6.3 10 3.1 0 Post basic Attachment Workshop Senior SOP Others Methods of learning cytotoxic drug handling
Figure 2: Staff nurses’ attitude towards safety related issues of cytotoxic drug handling
70 60.4 60
50 64 40 28.1 30.2 28.1 30
Percentage (%) Percentage 20
10 7.3
0 Able to tolerate a Able to tolerate a Worried about the Believing complete Feeling confident to certain level of certain level of long term side effects PPE use was handle cytotoxic drug improper practice improper practice of occupational unnecessary safely among their peers when they were busy exposure
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Discussion The mean score of nurses’ knowledge on cytotoxic drug handling (58.46 out of 100) was comparable to the pre- intervention score of a local study done in Sultanah Bahiyah Hospital, Kedah (45.4 out of 100)5. It was also comparable to the achievement of Turkish nurses (61.32%), but lower than the Cypriot (79.4%) in similar studies that assessed the nurses’ knowledge on cytotoxic drug handling6-7. This study found that cytotoxic drug handling of the majority of nurses were taught by senior staff (85.4%) and this method posed a risk of poor practice and knowledge to be passed on to future colleagues. Comparing with the other regions in the world, the percentage of nurses who handle chemotherapy in this hospital receiving formal post-registration education on chemotherapy is very low (6.3%). Studies in the UK hospitals showed 96% of the nurses who handles chemotherapy had formal post-registration training on chemotherapy, while hospitals in Pakistan and Cyprus had 37% and 18.2% respectively7-9. High knowledge level among the nurses is important to improve their adherence to the safety measures6. The results of this study also showed that some nurses may not have the right attitude towards safe handling guidelines of cytotoxic agents and were placing themselves and the others at the risk of cytotoxic exposure. These results were in line with findings of previous studies whereby nurses were not sufficiently trained to care for cancer patients and had poor understanding on safety-related issues of chemotherapy10-11. Therefore, more structured hands-on training and workshops on safe handling of cytotoxic agents should be conducted to build up the confidence and to raise awareness among the healthcare staff. Occupational Safety and Health Administration (OSHA) should play an active role in addressing this issue to protect health workers. As there was no significant correlation between the knowledge score on cytotoxic drug handling and the duration of nursing and cytotoxic drug handling experience , all staff handling cytotoxic drug must receive education and training on safe handling procedures prior to working with cytotoxic drugs. Continuous education and trainings are equally important. Written standard operating procedure (SOP) should be assessable to all relevant staff and should be updated in accordance with the latest guideline. Their safe handling competency and compliance should also be assessed on a regular basis. In addition, an open and effective knowledge-sharing environment among the healthcare staff should be promoted to empower them to make more informed safety and health decisions. The main limitation of this study was its small sample size. The findings may not be generalised to other settings as there are relatively small number of nurses working in wards that handle chemotherapy in this hospital. Nevertheless, this is the first study carried out in HTAR to assess the knowledge and attitude of safe handling of cytotoxic agents and these preliminary findings could serve as a benchmark for future interventions. It was a general survey of the knowledge and attitude of the nurses and may not reflect the actual practice in the ward. As the nurses’ adherence to cytotoxic handling guidelines were not measured in this study, clinical audit on practice can be done in future. 65
Conclusion This study showed that the knowledge and attitude on cytotoxic drug handling among the nurses in HTAR were just slightly above average. Majority of the nurses learned about cytotoxic drug handling from their seniors and only a handful of them received formal post-registration education on chemotherapy. The knowledge on cytotoxic safe handling was not correlated with the duration of nursing and cytotoxic drug handling experience. Continuous education and structured trainings are required to improve the knowledge and awareness on the appropriate handling of cytotoxic agents.
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Acknowledgement We are deeply indebted to our supervisors whose motivation and guidance helped us to complete this work. We would like to extend a special thanks to pharmacist Chan Huan Keat for allowing to use the survey questionnaires used in his previous research at Sultanah Bahiyah Hospital, Alor Setar. We would like to thank the Director General of Health Malaysia for his permission to publish this article. Finally, thanks to all who contributed towards this work.
Conflict of Interest Statement No external funding was received and the authors declared no conflict of interest.
References 1. Somayeh Hanafi; Hassan Torkamandi; Sahar Bagheri; Maria Tavakoli; Naser Hadav; Javadi, M., Safe Handling of Cytotoxic Drugs and Risks of Occupational Exposure to Nursing Staffs. Journal of Pharmaceutical Care 2015, 3 (1-2), 11-15. 2. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. http://globocan.iarc.fr/Default.aspx. 3. Elshamy K, E.-H. M., El-Roby M, Fouda M, Health hazards among oncology nurses exposed to chemotherapy drugs. African Journal of Haematology and Oncology 2010, 1 (3), 70-78. 4. Polovich, M.; Martin, S., Nurses' use of hazardous drug-handling precautions and awareness of national safety guidelines. Oncology nursing forum 2011, 38 (6), 718-26. 5. Keat, C. H.; Sooaid, N. S.; Yun, C. Y.; Sriraman, M., Improving safety-related knowledge, attitude and practices of nurses handling cytotoxic anticancer drug: pharmacists' experience in a general hospital, Malaysia. Asian Pacific journal of cancer prevention : APJCP 2013, 14 (1), 69-73. 6. Turk, M.; Davas, A.; Ciceklioglu, M.; Sacaklioglu, F.; Mercan, T., Knowledge, attitude and safe behaviour of nurses handling cytotoxic anticancer drugs in Ege University Hospital. Asian Pacific journal of cancer prevention : APJCP 2004, 5 (2), 164-8. 7. Kyprianou, M.; Kapsou, M.; Raftopoulos, V.; Soteriades, E. S., Knowledge, attitudes and beliefs of Cypriot nurses on the handling of antineoplastic agents. European journal of oncology nursing : the official journal of European Oncology Nursing Society 2010, 14 (4), 278-82. 8. Verity, R.; Wiseman, T.; Ream, E.; Teasdale, E.; Richardson, A., Exploring the work of nurses who administer chemotherapy. European journal of oncology nursing : the official journal of European Oncology Nursing Society 2008, 12 (3), 244-52. 9. Khan, N.; Khowaja, K. Z. A.; Ali, T. S., Assessment of knowledge, skill and attitude of oncology nurses in chemotherapy administration in tertiary hospital Pakistan. Open Journal of Nursing 2012, Vol.02No.02, 4. 10. Polovich, M., Nurses' Use of Hazardous Drug Safe Handling Precautions. Georgia State University: 2010. 11. Corner, J.; Wilson-Barnett, J., The newly registered nurse and the cancer patient: An educational 66 evaluation. International Journal of Nursing Studies 1992, 29 (2), 177-190.
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Scheduled Substances as a Cause Leading to Dangerous Drug Abuse
Zamrul Hisyam Noor1, Ahmad Aizat Zaini1, Mohd Hanif Mustafa1
1 Pharmacy Enforcement Branch, Pharmaceutical Services Division, Penang State Health Department, Ministry of Health Malaysia
Abstract
Introduction: Products containing scheduled substances such as psychotropic pills, cough medicines and Mitragyna speciosa (ketum) had been frequently abused. The widespread abuse of products containing scheduled substances was often perceived as less threatening compared to the pandemic issue of illicit dangerous drugs use. Nevertheless, in view of the easy access and frequent diversion of these products, there is a need to determine whether the abuse of these items had triggered more serious addiction problems involving more harmful drugs such as opiates and amphetamine-type substances (ATS). Objective: This study aimed to explore the factors of scheduled substances abuse and the role of scheduled substance abuse in the progression towards illicit dangerous drug use. Methods: Face-to-face interview sessions were held in Karangan Cure & Care Clinic, Kedah. Interviews were conducted until the point of data saturation. Interviews were audio-recorded, transcribed verbatim, and the data was analysed and grouped into themes. Results: Thirty clients were interviewed and 14 of them had experiences with scheduled substances abuse. Two main products containing scheduled substances – cough preparations (dextromethorphan and diphenhydramine) and ketum were most frequently abused by the subjects. The abuse was driven by several socioeconomic factors and catalysed by the easy access and affordability of these products. These scheduled substances caused dependence and withdrawal effects. Over time, the abuser may develop tolerance and need higher dose or stronger stimulants and therefore may lead to dangerous drugs use. Also, scheduled substances and dangerous drugs may be abused at the same time to obtain different effects, or used interchangeably when any of the items was unavailable. Conclusion: The easy access and affordability of scheduled substances may contribute to their abuse especially among the youths. The addictive potential of scheduled substances, although considered to be less hazardous, may eventually lead to the abuse of dangerous drugs.
Keywords: schedules substances abuse, kratom, ketum, Mitragyna speciosa, cough medicine, illicit use of dangerous drugs
67 NMRR ID: NMRR-16-1088-31354
Corresponding author: Ahmad Aizat Zaini Pharmacy Enforcement Branch, Pharmaceutical Services Division, Pulau Pinang State Health Department, Level 8, Federal Building, Anson Road, 10450 Georgetown, Penang. Email: [email protected]
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Introduction Illicit drug use is the use of psychoactive substances for purposes other than medical reasons. It is estimated that a quarter billion people used illicit drug globally. In 2013, 27 million people were suffering from drug dependence1. In Malaysia, there were 20,289 new cases of detected drug users in 2015, with a cumulative of 413,754 cases since 19882. In 2015, the National Anti-Drug Agency (NADA) reported that 20,295 youths were suffering from drug addiction problem, and this included children as young as seven years old, which illustrates the gravity of the phenomenon2. According to the same report, the top causes of addiction stated by the addicts were curiosity and peer pressure2. Most documented drug addicts were reported to be in the economically productive ages of 25 to 29 years old. As a consequence, the government spent more than RM 322 million in 2015 in managing the addictions2. The severity of addiction problem could have been the consequence of easy accessibility to the substances and reflects the emerging prescription and over the counter (OTC) drug abuse epidemic3. Scheduled substances such as Mitragyna speciosa (colloquially known as kratom, or ketum in Malay language), psychotropic pills and cough preparations are actively regulated by the Pharmacy Enforcement Division, Ministry of Health Malaysia under the provision of Poison Act 1952. Psychotropic pills and cough preparations are prescription and over the counter (OTC) items that are frequently the targets of diversion due to its easy access. As these items can be obtained legally, they are perceived to be of lower risk than the drugs obtained illegally. Prescription and OTC drug abuse has emerged as an alarming global problem4. In the United States, a survey in 2010 found approximately 2.4 million people were using prescription drug for non-medical purposes5. The survey also found that prescription drug abuse was most prevalent among youths aged between 18 to 25 years old5. It was reported that many teens believe that prescription drugs are safer because it is legal in the market and this contributed to the growing pandemic6. In view of the relatively high availability and frequent diversion of ketum, psychotropic pills and cough preparations, there is a need to determine whether and to what extend the abuse of these items had triggered more serious addiction problems involving more harmful drugs such as opiates and amphetamine-type substances (ATS). The objective of the study was to explore the factors of scheduled substances abuse and the role of scheduled substance abuse in the progression towards illicit dangerous drug use.
Methods The study was carried out between February 2016 and December 2016. The sample of the study includes a group of clients who are receiving treatment at the Karangan Cure & Care Clinic, Kedah. Cure & Care clinics are facilities providing voluntary rehabilitation and drug addiction recovery services that are managed by the NADA Malaysia. The study included clients aged 18 years and above and was actively under the follow-up of Karangan Cure & Care Clinic, Kedah during the study period. Clients who refused to participate in the study, clients with mental condition compromised by previous 68 history of substance abuse and clients who possessed below average or limited communication skills were excluded from the study. Phenomenological approach in qualitative analysis was used in this study. The selection of interviewees was based on convenience sampling and the participants were chosen at random by the facilitator. The clients were interviewed until the point of saturation is reached and no new information is obtained. Data was collected through face-to-face interview by using an interview guide involving four interviewers in one occasion. The interview sessions lasted between 2 to 15 minutes. All interviews were audio recorded after getting signed consent from the clients. The interviews were kept as audio files. The audio records of the interviews were then transcribed verbatim. This was followed by
68 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 verification process by the interviewers. The data obtained were then coded and organised into themes which were then interlinked in order to construct a theoretical framework. In this study, scheduled substances befits the definition of ‘Poison’ as per outlined in the Malaysian Poison Act 1952 (Act 366) which stated that ‘any substance specified by the name in first column of the Poisons List (First Schedule) and includes any preparation, solution, compound, mixture or natural substance containing such substance, other than an exempted preparation or an article or preparation included for the time being in the Second Schedule’. Meanwhile, dangerous drug is defined as per outlined in Malaysian Dangerous Drug Act 1952 (Act 234) which stated that ‘any drugs or substances which is for the time being comprised in the First Schedule (of this act)’ 7.
Results Demography Thirty clients aged between 18 and 21 (mean=19.5) years old were interviewed, in which 14 clients (C1-C14) had experiences with scheduled substances abuse. All these 14 participants were male, and 13 of them were of Malay ethnicity. Out of these 14 clients, most of them (11 clients) completed secondary school and the highest qualification was technical certificate from local skills development institute (2 clients). Majority of the clients (9 clients) were from suburban area and about half (8 clients) of them are from underprivileged families. Patients’ demographic characteristics were summarised in Table 1. Most of the interviewees were involved with drugs during their secondary school period, but several were as early as 11 years old. Generally, the clients were from families with parents of working group category with moderate to low income earnings.
Table 1: Demographic characteristics of clients with experience of scheduled substances abuse (N=14) Characteristics n (%) Ethnicity, n (%) Malay 13 (92.9) Indian 1 (7.1) Education level, n (%) Technical certificate 2 (14.2) Secondary 11 (78.6) Primary 1 (7.1) Locality, n (%) Urban 5 (35.7) Suburban 9 (64.3) Family socioeconomic status, n (%) 69 Subpar 8 (57.1) Moderate 6 (42.9) Affluent 0 (0)
Thematic content analysis The thematic content analysis identified five major themes namely factors triggering substance abuse, accessibility and affordability of scheduled substances, type of scheduled substances used and illicit abuse of dangerous drug, dependence or habit-forming effects and lastly the ramification of the substance addiction. Descriptive of each theme with illustrative excerpts from the interviews between the clients (C) and interviewers (I) were as the following.
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Theme 1: Factors triggering scheduled substance abuse Peer influence and curiosity has been reported as the main causes of involvement in drug abuse in which the clients said: C5: I first became involved with drugs because (I was) influenced by a friend. I just knew that friend...but out of curiosity... After I tried, I became addicted. C8: Influence from friends, after hanging out (with them) I feel the urge to try. After that (I) want to try other things.
Besides that, the clients also admitted taking it for recreational use, for its euphoric and dissociative effect as well as an energy boost to perform more physical works. C8: (I take the substances) just for fun. (Just for) Excitement. C10: Our body will become sleepy, become ‘high’. C3: (So that) When (I) do work (I would) become energetic.
In addition, consumption of certain scheduled substances such as ketum is perceived as socially acceptable and not deemed harmful due to the fact that it is commonly and openly consumed by the public, especially among the communities of which the interviewees belong to. C7: Many are taking it. (Many) Villagers (are) taking it. (Especially) ketum.
Theme 2: Accessibility and affordability of the scheduled substances Scheduled substances are easily accessible mostly due to illicit scheduled substances supply activities by health care providers such as clinics and pharmacies. According to the clients, sometimes scheduled substances such as cough medications were sold with minimal restrictions by some pharmacies and clinics, resulting in easy and continuous supply of scheduled substances intended for abuse. The clients had also attributed the constant supply of scheduled substances to their network of friends and acquaintances. The multiple sources or sellers of these substances ensured virtually limitless supply and opened up more opportunities for scheduled substances abuse. C1: Nowadays there are many places selling. Easy (to get). C4: Cough medicine can be obtained from clinic and pharmacy. Easy to get. I buy 3 bottles at a time. C9: Cough medicines, ah, I ordered them from my friends. C12: A lot of pharmacies, a lot. A lot of pharmacies are selling (cough medicines). C14: You can get it (ketum) anywhere you go.
Besides that, scheduled substances were relatively cheap and thus making it affordable and prone to abuse. C3: (Ketum) are sold at RM5.00 per packet. For smaller packets it is sold at RM 3.50 and RM 2.50. 70 C8: Ketum are obtained from nearby (seller). It is cheap, RM5.00. Cough medicine RM7.00 (per bottle). Dynadryl (diphenhydramine) RM7.00, Nospan (dextromethorphan) are RM0.70 per tablet.
The supply of cough medicines without proper screening and assessment by some healthcare professionals could imply the compromises they sometimes made against their professional ethics and social responsibilities. This may have contributed to the ubiquity of the scheduled substances for abuse. C7: (If you) Go frequently also they (will) sell, (if you are) not coughing also they (will) sell. C8: The largest amount I used to buy was 20 tablets (Nospan), 2 bottles of cough medicine. (Even though I) Went everyday also the pharmacy (will) sell. 70 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018
According to most of the clients interviewed in this study, ketum is stated as the easiest scheduled substance to be acquired as it could be agriculturally cultivated and self-prepared without having to depend on the supplier. C12: Sometimes I boil (the ketum leaves) myself. I plant the tree. I: When did you start taking ketum? At 13 years old? When you were 13 years old? C3: (Nod in agreement).
Theme 3: Type of scheduled substances abused and illicit use of dangerous drug Upon questioning on types scheduled substances abused by the clients (if any), most of them admitted taking ketum. C3: At first I smoke cigarette. After that I take ketum. C11: I drink ketum.
Besides ketum, cough medicines were also frequently abused. Two types of cough medicines were commonly abused which were antitussive such as dextromethorphan (Nospan) tablet and expectorants such as diphenhydramine (e.g. Benadryl, Dynadryl, Uphadyl) cough syrups. The cough medicines are usually either consumed alone or mixed together with ketum. C12: At first I take Nospan. C6: I usually take ketum mixed with cough medicines.
During the interview, clients had described ketum as a stimulant by nature and reported to increase alertness and energy level of the consumer. However, mixture of cough medicines and ketum is claimed to produce different sensation as it will exert numbness, drowsiness and increase the potential for dissociative or hallucinogenic effect on the abuser. C10: After I take ketum (I) cannot sleep. It’s energetic. If heroin it causes sleepiness. (When I take) ketum with cough medicine it will cause sleepiness. (Taking) Ketum alone will not cause sleepiness. (My) Body feels energetic. When mixed (with cough medicine) (my) body (will) become numb and drowsy.
In this study, none of the clients mentioned involvement in the abuse of psychotropic pills such as drugs of benzodiazepine class or any opioid substances. When probed further on their history of scheduled substance use, almost all clients admitted of being involved in scheduled substances abuse prior to shifting to the illicit use of dangerous drugs. C3: I took it (ketum) for a while, about 10 months. (I) Drank ketum. After that I stopped. I stopped and then I switched to ‘medicine’ (heroin). C4: I took heroine (after ketum). C10: (I took ketum) For about 2 months, and then I started taking methamphetamine. 71 C13: And then, umm, after (taking) cough medicine, I took ice (methamphetamine).
In terms of dangerous drugs, the most abused drugs reported by the clients were heroin followed by methamphetamine, cannabis (ganja) and benzodiazepines. When clarifying on the shift from scheduled substance use to illicit dangerous drug use, one of the clients explained that the use of dangerous drugs is to step up the euphoria achieved from previous scheduled substance abuse. C11: I searched for it (heroin) by myself. (Just) Drinking ketum is not satisfying.
A few clients stated that the use of dangerous drugs can fill the gap due to absence of scheduled substance and act as a replacement for scheduled substances abuse, while several others were taking them for recreational purposes. It was also found that many of them abused multiple 71 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 substances at the same time instead of abusing just one particular substance exclusively. The clients claimed that different substances would give different effects. Consuming multiple types of substances also enabled them to adapt with product unavailability. C3: (from ketum to heroine) There was shortage of ketum supply. C8: (from ketum to ganja) I just tried everything.
Theme 4: Dependence / habit-forming effects During the interview, the clients were asked if scheduled substances being abused were able to induce addiction. Scheduled substances, especially ketum, were reported to create constant urge for the substance among the abusers, resulting in the prolonged use of ketum and led to dependence. Several clients claimed ketum consumption affected their social and occupational functionality. C4: Previously I took ketum to help me with my work. If it is absent, I could not lift even slightly heavier loads. I was working at a sawmill back then. I could lift 20, 30 kilo(gram) loads (with ketum). C9: (Without ketum) I cannot do any work, I will keep sleeping.
Attempts to stop ketum consumption were futile and the urge to consume the scheduled substances were reported to be irresistible. C7: The hardest one to stop taking, ketum. C8: No, if I do not take it (cough medicine), I feel ‘empty’, I must take it.
Additionally, many of the clients informed that ketum and cough medicines caused dependence and withdrawal effects when the substances were not taken. Some of the clients even described that the withdrawal effect of taking ketum is comparable to and at times, worse than the withdrawal effect induced by heroine. C1: (When not taking ketum), I will feel headache and unhappy. C4: (Ketum) got (withdrawal effect), feeling ill similar to heroine. C5: When I drink (ketum), and after a while when the effect weaned off, my body will become shaken and starts sweating. C6: Ketum addiction is worse than heroine. It causes vomiting. (I) cannot wake up and feel that my body cannot do anything. (If) heroine, feels like feverish and chill, after long bath (I will) feel okay and then after around five minutes it (will) recur.
Abusing scheduled substances also led to a more serious addiction problem involving dangerous drugs because over time, the abuser will develop tolerance and need higher dose or stronger stimulants. C4: One day (abuser) will (need to) take stronger drug, because I already take ketum, for example two Coca-Cola’s bottles (size) daily, (it is) not enough, I feel want to take 72 heroine, because heroine and ketum, the euphoric effect is almost the same.
Theme 5: The ramification of substance addiction According to the interview, our clients were aware of the detrimental effects of substance abuse, but it was preceded by the stronger desire to have fun and feel the euphoric effects. C6: Before started (consuming) I did think about health (concern). But once tried, I do not care about (the) harm anymore, just think about fun.
Once they were involved in substance abuse, the clients admitted that they were hooked in the void of addiction and could not overcome the desire. C4: If (we) talk about drugs, it is never (enough to) satisfy. 72 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018
One of the clients had admitted that he had frequent asthma attack when he was involved in substance abuse but his health deterioration did not stop his addiction to substance abuse. C8: I used inhalers before (when taking drugs), but now I’m not taking any drugs, my heart (lungs) feels fine. If not, I have to use inhalers.
The clients however did express their regrets trying those substances and became hooked in addictions that cost them their future. C2: Thinking back… (I) feel regret. C4: Of course regret…Regret. Now (I am) already 22 years old, not going to college but admitted to the (rehabilitation) centre.
Discussion The abuse of scheduled substances involving prescription and OTC medicines is well noticed globally. The ubiquity and high accessibility to the substances were reported by several studies as the main factors of scheduled substances abuse8,9,10. Although studies on scheduled substances abuse had been done both globally and locally, the link between scheduled substance (prescription or OTC products) abuse and dangerous drugs use in the Malaysian setting needs further probing and discussion. This is deemed necessary to better address and reduce the number of individuals falling into dangerous drug use, which is still reported at an alarming level2. The interviews showed that ketum and cough medicines were the most popular options for scheduled substance abuse. The use of scheduled substances, akin to other social problems, did stem partly from peer pressure. Almost all clients pointed to their social circle as their starting point of involvement in the substance abuse. Several clients relied on their networking as an efficient medium in obtaining the substances for recreational use. The clients had also suggested that substances abuse is part of their social activities and therefore they were inevitably enticed into trying and were eventually hooked on scheduled substances abuse. Ketum use in this group of client was believed to be influenced by the geographical location and socio-demography of the interviewees as ketum is a native tropical plant and is vastly available in the northern territories of Malaysia11. Similar pattern of ketum popularity in the North Malaysia had been shown in another study, especially in the suburban areas12. Ketum (Mitragyna speciosa) contains mitragynine and 7-hydromitragynine, both are alkaloids which are responsible in producing the opioid-like effects on its consumer13. Even though mitragynine has been listed as a regulated substance in 2003, ketum is still commonly used, sold and purchased among the community as it had been consumed freely for generations without any stigma14. This was confirmed by several clients in this study, as they mentioned that ketum is openly consumed in their communities with minimal concern on its psychoactive effects and long-term repercussions. Traditionally, ketum had been used for multiple purposes such as treatment of minor ailments 73 like cough and diarrhoea, but was more popularly consumed for energy boost and pain management15,16. This had made ketum consumption more prevalent among the suburban communities in northern Malaysia, where most of our subjects were from, due to their economic orientations that focus on laborious tasks and their close proximity to the natural habitat of the plant. As stated by several clients, their source of ketum was mostly from the commoners in their local community who plant ketum by themselves. In order to increase its palatability and improve the ‘high’ obtained from the substance, ketum is often concocted with carbonated drinks and cough medicines, respectively. The youths of suburban districts from low to moderate income family who completed below average education level are among those most vulnerable to the abundance and affordability of ketum drinks in the fairly unregulated market. According to our group of participants, ketum is the best option for energy boost in order to commit to their low-paying and strenuous job, which is parallel to 73 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 previous findings17. Often, this leads to substance dependence and even tolerance, which may escalate to the abuse of substances with higher potency. Cough medicines, on the other hand, had always been notorious for their misuse and recreational use to achieve euphoria especially among the youth18,19. Several studies on cough medicines abuse and diversion, especially those containing Dextromethorphan (Nospan) and Diphenhydramine (Benadryl, Uphadyl, Dynadryl), had been published at the international level. In the United States, cough medicines are the main option for substance abuse among the adolescents20. Our study found most of the clients admitted intentional misuse of cough preparations. The relatively easy access and affordability of cough preparations were the two main factors which contributed to its rampant abuse. Previously, similar finding had also attributed the widespread misuse of cough medicines to the product legality and its cheap price tag9. In Malaysia, the active ingredients of frequently abused cough medicines are categorised as Poison under the Poison Act 1952, which means that these are controlled items and can only be sold by licensed pharmacists and medical practitioners. Despite this, current regulation does not seem to impede the supply of cough medicines to be used for recreational purposes. Statements obtained from several clients in this study suggested that getting constant supply is not difficult, as they admitted that some clinics and pharmacies supply cough medicines in large quantities and without thorough medical assessment prior to the supply. This suggested that unless the healthcare malpractice and lack of social responsibility observed among this fragment of healthcare practitioners are rectified, issues of recreational use of scheduled substances such as cough medicines will remain unsolved. Clients also admitted to ‘pharmacy- or clinic-shopping’, which means acquiring stocks from multiple premises in order to ensure continuous supply of cough medicines. This inappropriate supply of cough medicines could be addressed through a two-pronged approach: a more regular monitoring and enforcement activities and incorporating an automated supply tracking system and registry that is able to monitor distribution and supply of these scheduled substances effectively. In terms of substance dependence, scheduled substances were described to be both habit- forming and addictive, although the dependency of cough medicines was regarded to be milder. All clients admitted that ketum elicited addiction and triggered withdrawal symptoms including restlessness, muscle pain and sweating. Some complained of shivering when the effect of ketum weaned off. The noxious experience and degree of severity of withdrawal symptoms varied from one client to another. However, every client who had experienced ketum abuse in our group admitted that stopping ketum consumption was not an easy task and for some clients, the amount and frequency of ketum consumption had continued to gradually increase prior to rehabilitation. Previous studies had shown withdrawal effects and tolerance from long term use of ketum, aside from its negative effects on the cognitive behaviour of the users21,22. From another perspective, the ability of ketum alkaloid to mimic opioid activity by stimulating opioid receptors proposed its therapeutic potential to be used as proper analgesics and as an opioid replacement therapy14,23. However, this needs to be cautiously considered as the therapeutic potential comes together with the possibility of abuse and its exact 74 pharmacological activity in long-term ketum abusers still requires further assessment17,24. Cough medicines are portrayed as possessing less addictive potential comparing to ketum. Nevertheless, several studies argued that even though cough medicines do not cause addiction pharmacologically, the ability to produce mental dissociation and euphoria is largely sought after by the abusers10,25. Eventually, recurrent consumption of cough medicines to alter the mental states could cause substance dependence in the long run. This was found to be coherent with our findings as the clients related their recreational use of cough medicines with their need to feel ‘dizzy’, colloquial for induced euphoria. Prolonged use of cough medicines for this purpose exposed users to harms secondary to altered mental state such as accidents and substance overdose that may lead to fatality26, 27.
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Almost half of the approached Cure & Care Clinic clients had experience or were involved in scheduled substances abuse prior to their use of dangerous drugs, which eventually led them to rehabilitation. Therefore, scheduled substances may play a significant part in the transition to dangerous drugs use. Our results revealed that the involvement in dangerous drugs was also related to the influence posed by the same social circle that embroiled them into scheduled substance abuse. The same group of friends opened the access to the supply of dangerous drugs, either by acting as a direct stockist or by sharing known illicit suppliers. The shift to dangerous drugs use could be a result of the curiosity to try ‘stronger’ substances, which was ultimately traced back to the social circle. On top of that, the similar sensation elicited by ketum and heroine may also contribute to the transition from scheduled substance abuse to dangerous drug use. As ketum and heroine can be used interchangeably to obtain the desired mental and physical state or to fulfil the cravings due to substance dependence, this provided options for the abusers when they face stock shortage of either substance. The main limitation of this study was that this was a single-centre study that may not be able to represent the general population in Malaysia. Also, we were unable to ensure that absolute truth was obtained from the verbal conversations during the interviews as the clients might be inclined to give answers which they perceive as favourable or more socially acceptable. During the interviews, four interviewers held distinct, non-scripted interviews simultaneously guided by an interview guide which acted as the framework for the interviews. Nevertheless, the results obtained from the interviews were dependent on the individual styles and skills of the interviewers in handling the conversation and on the responsiveness of the clients. As this study was qualitative and explorative in nature, it is recommended that further quantitative study at the national level is necessary to evaluate the impact of the scheduled substances abuse towards the dangerous drugs use.
Conclusion The role of scheduled substances abuse in leading to dangerous drug use has not been previously discussed. The relatively easy access to scheduled substances, along with its inexpensive price tag made it an easy target for recreational use and abuse especially among the youths. This study found that the addictive potential of scheduled substances, although often deemed to be less hazardous, may eventually result in the abuse of dangerous drugs. The qualitative and explorative nature of this study warrants further detailed investigations on the impact of scheduled substances abuse towards drug addiction catastrophe to gain a better perspective on the issue.
Acknowledgement We would like to express our gratitude to Professor Dr Mohamed Azmi Ahmad Hassali from the School of Pharmaceutical Sciences (Discipline of Social and Administrative Pharmacy) for taking his valuable time to share his expertise and experiences in qualitative research throughout the course of the research. Appreciations are also given to our colleague, Dr Muthu Kumar a/l N.S Murugiah (Senior 75 Principal Assistant Director, Penang Pharmaceutical Services Division) for his input and comments in improving the quality of the research. We would also like to thank the Director General of Health Malaysia for his permission to publish this article.
Conflict of Interest Statement No external funding was received and the authors declared no conflict of interest.
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References
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21. Singh, D., Müller, C. and Vicknasingam, B. Kratom (Mitragyna speciosa) dependence, withdrawal symptoms and craving in regular users. Drug and Alcohol Depend, 2014, 139, 132- 137. 22. Yusoff, N., Suhaimi, F., Vadivelu, R., Hassan, Z., Rümler, A., Rotter, A., Amato, D., Dringenberg, H., Mansor, S., Navaratnam, V. and Müller, C. Abuse potential and adverse cognitive effects of mitragynine (kratom). Addict Biol, 2014, 21(1), 98-110. 23. Takayama, H. Chemistry and pharmacology of analgesic indole alkaloids from the rubiaceous plant, Mitragyna speciosa. Chem Pharm Bull (Tokyo), 2014, 52(8), 916–928. 24. Hassan, Z., Muzaimi, M., Navaratnam, V., Yusoff, N.H., Suhaimi, F.W., Vadivelu, R., Vicknasingam, B.K., Amato, D., von Hörsten, S., Ismail, N.I., Jayabalan, N., Hazim, A.I., Mansor, S.M., Müller, C.P. From kratom to mitragynine and its derivatives: physiological and behavioural effects related to use, abuse, and addiction. Neurosci. Biobehav. 2013, 37, 138–151. 25. Melick-Shield, J., Barloon, D., Liesveld, J. Dependence risk with chronic dextromethorphan abuse. Current Psychiatry, 2005, 4(2), 13–16, 22–23. 26. Miller, S. Dextromethorphan psychosis, dependence and physical withdrawal. Addict Biol, 2005, 10(4), 325-327. 27. Murray, S. and Brewerton, T. Abuse of over-the-counter dextromethorphan by teenagers. South Med J, 1993, 86(10), 1151-1153.
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Study of Traditional and Complementary Medicine (TCM) Usage among Cancer
Patients Receiving Chemotherapy in Hospital Melaka
Wong Kuo Zang1, Mastria Mohamed1, Loh Wan Ting1, Suhadah Ahad1
1 Hospital Melaka, Ministry of Health Malaysia
Abstract
Introduction: Traditional and complementary medicine (TCM) is commonly used among cancer patients. Objective: The aim of this study was to determine the prevalence, types, reasons and belief of TCM use among cancer patients receiving chemotherapy in Hospital Melaka. The study also compared the delay in seeking conventional treatment, chemotherapy adherence and satisfaction level of conventional treatment between TCM users and non-TCM users. Methods: This was a cross-sectional study where data was collected from August to December 2016. A total of 141 cancer patients who were receiving chemotherapy at Hospital Melaka were recruited with written consent. All patients were directly interviewed with a structured questionnaire. The data were analysed using chi-square test and independent t-test in SPSS version 22.0 software. Results: In this study, 68.8% respondents were TCM users. Types of TCM found to be commonly used were soursop fruits and leaves (42.27%), apricot seed (28.87%), butterfly wing leaf (26.80%) and Sabah snake grass (25.77%). The main reason of TCM use was to suppress the progression of cancer (77.30%) and most of them believed that TCM is able to do so (69.90%). TCM usage was associated with ethnicity and household income. Between TCM users and non-TCM users, there were significant differences in the number of weeks delay in seeking conventional treatment and satisfaction toward conventional treatment (p<0.01) but no significant difference in delay of chemotherapy schedule. Conclusion: There was a high prevalence of TCM use among cancer patients receiving chemotherapy in Hospital Melaka and they believed that TCM can suppress the progression of cancer. The results also showed that the most commonly used TCM was Soursop fruits and leaves. TCM use may be contributing to delays in seeking conventional treatment but did not affect chemotherapy adherence. Non-TCM users had higher satisfaction level toward conventional treatment compared with TCM users.
Keywords: traditional and complementary medicine, TCM, cancer, chemotherapy, adherence
78 NMRR ID: NMRR-16-1255-31588
Corresponding author: Wong Kuo Zang Department of Pharmacy, Hospital Melaka, Jalan Mufti Haji Khalil, 75400 Melaka Email: [email protected]
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Introduction Cancer is the principal cause of death worldwide1. Based on the Malaysian National Cancer Registry (NCR) report 2007-2011, a total of 103,507 new cancer cases were diagnosed in Malaysia in the 5- year period2. Traditional and complementary medicine (TCM) is a form of health-related practice designed to prevent, treat, manage illnesses or preserve the mental and physical well-being of individuals. It includes practices such as traditional Malay medicine, Islamic medical practice, traditional Chinese medicine, traditional Indian medicine, homeopathy and complementary therapies, and excludes medical or dental practices utilised by registered medical or dental practitioners3. Nutritional therapy is described as a system of healing based on the belief that food provides the medicine we need to obtain and maintain a state of health whereby our food is our medicine4. Previous studies conducted in Asian countries as well as in Malaysia showed high prevalence rate of TCM use among cancer patients5-11. However, the effectiveness and safety of using TCM upon diagnosis and in combination with conventional cancer treatment are the concern of breast surgeons, oncologist and the health care team9. Besides, TCM use was also found to be associated with delay in seeking conventional treatment among breast cancer patient which led to high incidences of progressive breast cancer and a low survival rate among Malaysian women with breast cancer12-13. A study that was done in Malaysia showed that 16.4% of cancer patients stopped the standard treatment while using TCM8. Cancer patients generally perceive cancer as more frightening and less controllable compared to other chronic or life-threatening diseases. Thus, it is important for the healthcare provider to understand the factors motivating them to use TCM14. This study examined the prevalence, types, reasons and belief of TCM use among cancer patients receiving chemotherapy. It also compared TCM users and non-TCM users on the delay in seeking conventional treatment, chemotherapy adherence and satisfaction level of conventional treatment.
Methods This study was a cross-sectional study conducted among patients whom had solid tumor or hematology malignancies that were receiving chemotherapy in wards or day care centre of Hospital Melaka, Malaysia. Approval to conduct the study was obtained from the Medical Research & Ethnic Committee (MREC), Ministry of Health Malaysia with registration identity NMRR-16-1255-31588. Data was collected from August to December 2016. All patients who fulfilled the inclusion criteria were recruited into the study. Participation in this study was voluntary with written informed consent. All participants were assured of their confidentiality and the right not to participate or to withdraw at any point during the study. All participants were directly interviewed using a structured questionnaire. The questionnaire was in English and was extracted from a previous study “An Empirical Study on Traditional, Complementary and Alternative Medicine Usage among Malaysian Cancer Patients” by Nagashekhara et al. (2015). The permission to use the questionnaire had been obtained from the authors5. 79 Data were analysed using the Statistical Package for the Social Sciences (SPSS) version 22.0. Association between socio-demographic characteristics and TCM use were assessed using chi- square test. Independent t-test was carried out to determine if there was any significant difference between TCM users and non-TCM users in the delay in seeking conventional treatment, chemotherapy adherence, and satisfaction level of conventional treatment and healthcare professional’s influence.
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Results Demographics The characteristics of included patients were presented in Table 1. A total number of 141 respondents were interviewed whereby 94 (66.7%) were female and 47 (33.3%) were male. The mean age of respondents in this study was 52.3 (standard deviation (SD) 13.8) years old with maximum age of 74 years old and minimum age of 18 years old. There were 97 (68.8%) TCM users and 44 (32.2%) non- TCM users. The mean age was 51.7 (SD 13.9) years old and 53.4 (SD 13.7) years old for TCM users and non-TCM users respectively. Majority of the respondents were Malay (65.2%), married (82.3%), with secondary education (44.7%), student (52.5%), monthly income in the range of RM0-RM2000 (67.4%) and living in rural area (58.9%). Among the respondents, 32 (22.7%) had breast cancer, 24 (17.0%) had non-Hodgkin lymphoma and 17 (12.1%) had ovarian cancer. Among all the socio-demographic variables, TCM use was found to be associated with ethnicity (χ2(2)=21.275, p<0.01) and household monthly income (χ2(3)=8.684, p<0.05), in which Malay and higher income patients had higher usage of TCM.
Types of TCM used The most frequently used TCM among respondents were soursop fruit or leaf (42.3%) followed by apricot seed (28.9%), butterfly wing leaf (26.8%) and Sabah snake grass (25.8%) as presented in Table 2.
Reason, belief and perception of TCM use Most of the TCM users stated that the reason of using TCM was to suppress the progression of cancer (77.3%) and to improve physical well-being (70.1%). More than half of TCM users (69.9%) believed that TCM could suppress the progression of cancer and 53.7% users believed that TCM would not cause any unwanted side effects as it is ‘natural’. However, only 3.1% TCM users believed that TCM is more effective than the conventional treatment and 25.7% TCM users believed that TCM is safe to use together with conventional treatment. Moreover, it was noted that more than half of TCM users (60.8%) did not disclose to their doctors that they are using TCM. Among the TCM users, 48.5% said that TCM is somewhat helpful for their cancer followed by 21.6% somewhat not helpful, 20.6% very helpful and 9.3% not at all helpful. On the other hand, non-TCM users stated that they did not use TCM because they had never thought of using it (84.5%), satisfied with conventional treatment (82.2%), did not believe in its efficacy (71.1%) as well as discouragement from family, friends and doctors (68.9%). As shown in Table 3, there were significant differences in the mean duration delayed in seeking conventional treatment (9.7 weeks versus 2.4 weeks, 95% confidence interval (CI) 2.683, 11.808) and patient’s satisfaction score with conventional treatment (mean difference -8.488, 95% CI 10.201, 6.775) between TCM users and non-TCM users. There was no significant difference in the mean frequency of delayed chemotherapy between TCM users and non-TCM users. 80
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Table 1: The socio-demographic and clinical characteristics of TCM and non-TCM users (N=141) Variables, n (%) All TCM user Non-TCM user
Total respondents 141 97 (68.8) 44(31.2) Gender Female 94 (66.7) 68 (70.1) 26 (59.1) Male 47 (33.3) 29 (29.9) 18 (40.9) Ethnicity* Malay 92 (65.2) 75 (77.3) 17 (38.6) Chinese 39 (27.7) 19 (19.6) 20 (45.5) Indian 10 (7.1) 3 (3.1) 7 (15.9) Marital status Single 18 (12.8) 12 (12.4) 6 (13.6) Married 116 (82.3) 82 (84.5) 34 (77.3) Divorced or separated 7 (5.0) 3 (3.1) 4 (9.1) Education level Never 12 (8.5) 5 (5.2) 7 (15.9) Primary 47 (33.3) 30 (30.9) 17 (38.6) Secondary 63 (44.7) 46 (47.4) 17 (38.6) Tertiary 19 (13.5) 16 (16.5) 3 (6.8) Employment status Employed 1 (0.7) 1 (1.0) 0 Student 74 (52.5) 48 (49.5) 26 (59.1) Unemployed 26 (18.4) 17 (17.5) 9 (20.5) Retired 6 (4.3) 6 (6.2) 0 Self-employed 34 (24.1) 25 (25.8) 9 (20.5) Household monthly income* 0 - 2000 95 (66.7) 60 (61.9) 35 (79.5) 2001 - 4000 30 (21.3) 21 (21.7) 9 (20.4) 4001 - 6000 14 (9.9) 14 (14.4) 0 > 6000 2 (1.4) 2 (2.1) 0 House location Rural 83 (58.9) 59 (60.8) 24 (56.8) Urban 58 (41.1) 38 (39.2) 20 (43.2) Comorbidity Yes 71 (50.4) 48 (49.5) 23 (52.3) No 70 (49.6) 49 (50.5) 21 (47.7) Supplement taken before cancer Yes 55 (39.0) 42 (43.3) 13 (29.6) No 86 (61.0) 55 (56.7) 31 (70.5) Cancer stage Stage 1 7 (5.0) 7 (7.2) 0 Stage 2 27 (19.1) 18 (18.6) 9 (20.5) 81 Stage 3 35 (24.8) 24 (24.7) 11 (25.0) Stage 4 34 (24.1) 26 (26.8) 8 (18.2) Unclassified 27 (19.1) 15 (15.5) 12 (27.3) Unknown 11 (7.8) 7 (7.2) 4 (9.1) Satisfied with conventional treatment Yes 120 (85.1) 81 (83.5) 39 (88.6) No 12 (8.5) 9 (9.3) 3 (6.8) Not sure 9 (6.4) 7 (7.2) 2 (4.5) * association between variables and TCM use was observed (Chi-square test)
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Table 2: Types of TCM used Non-pharmacological, n (%)
Tai chi 3 (3.1) Aromatherapy 1 (1.0) Ceragem bed 3 (3.1) Relaxing exercise 1 (1.0) Massage 3 (3.1) Qi Gong 1 (1.0) Yoga 1 (1.0) Pharmacological, n (%) Soursop fruit or leaf 41 (42.3) Lingzhi 3 (3.1) Apricot seed/ Vitamin B17 28 (28.9) Miracle water (Air Ajaib) 3 (3.1) Butterfly wing leaf 26 (26.8) Lemon/ morning elixir 2 (2.1) Sabah Snake grass 25 (25.8) Stem cell product 2 (2.1) Habbatus Sauda /Black seed 10 (10.3) Olive oil 2 (2.1) Traditional Malay Medicines 8 (8.3) Royal jelly 1 (1.0) Traditional Chinese Medicine 7 (7.2) Ginseng 1 (1.0) Nutritional beverages 7 (7.2) Jering/ Jenkol 1 (1.0) Vitamins and minerals tablet 6 (6.2) Hydrogenised drinking water 1 (1.0) Antioxidant capsule/tablet 5 (5.2) Rodent tuber 1 (1.0) Honey 5 (5.2) Beet root 1 (1.0) Pomegranate fruit 5 (5.2) Date palm 1 (1.0) Unknown product 5 (5.2) Betel 1 (1.0) Alkaline water 4 (4.1) Homeopathy 1 (1.0) Spirulina 4 (4.1) Traditional Indian Medicine 1 (1.0) Chorella 3 (3.1)
Table 3: Comparisons between TCM users and non-TCM users (N=141) TCM users Non-TCM Mean difference Variables (n=97), users (n-44), P-value (95% CI) mean (SD) mean (SD) Patient’s satisfaction score with -8.488 20.2 (6.68) 28.7 (3.57) 0.000 conventional treatment (10.201, -6.775) Number of weeks delayed in seeking 7.245 9.7 (21.06) 2.4 (5.50) 0.002 conventional treatment (2.683, 11.808) 0.066 Frequency of chemotherapy delayed 0.13 (0.45) 0.07 (0.33) 0.385 (-0.084, 0.215)
Discussion This study showed high prevalence of TCM use among cancer patients in Hospital Melaka which 82 supported the findings of other studies done in Malaysia5,7,8,15. TCM use has become more common and widely acceptable among cancer patients. This could be that chronic, painful, debilitating or fatal conditions such as cancer are perceived more frightening than other chronic or life-threatening diseases and led to high usage of TCM16,17. Studies conducted in other Asian countries reported a high prevalence of TCM use as well. For example, the prevalence of TCM use was 60.9% in Thailand, 55% in Singapore, 60.9% in Palestine and 93.4% in China6,10,11,18. A meta-analysis of 152 studies from 18 western countries such as New Zealand, United States, Australia, Canada and the Europe reported that the combined prevalence for current use of TCM across all studies was 40% which is lower than this study19. This could be explained by the differences in culture and religions across the population as well as different definitions of TCM6,8. Ethnicity and household monthly income were found to be associated with TCM usage in this study. This was supported by the findings of Raja Lexshimi RG et al. in 2013 whereby high prevalence 82 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 of TCM use was found among the Malay and Chinese ethnic groups9. A few studies observed that TCM users tend to be higher earners as TCMs are more affordable to this group of population6,9,20,21. For other socio-demographic variables, conflicting findings have been reported. Several studies in Malaysia reported education level was linked to higher prevalence of TCM use7,8,20,21. It was suggested that better educated patients tend to be more critical towards conventional therapy and are more aware of TCM treatment. However, some other studies had reported similar findings to the present study that education level is not associated with TCM usage 6,9. In this study, TCM was classified into pharmacological and non-pharmacological treatment and it was found that the usage of natural products was much higher than the others. The four most popular natural products were soursop fruit and leaf, apricot seed, butterfly wing leaf and Sabah snake grass. A study by Raja Lexshimi RG et al. in 2013 found that nutritional supplements (41.8%), herbal products (40.2%) and multivitamin (33.6%) were the most frequently used TCM, and Sabah snake grass was identified the most commonly used herbs among the herbal products9. Soursop fruit is also named Graviola. Several laboratory studies reported that soursops have beneficial effects such as anticonvulsant, antiparasitic, anti-arthritic, antimalarial, antidiabetic, hepato- protective and anticancer. Furthermore, soursop extracts were reported to have significant anti-cancer properties in a number of cancer cell lines both in vitro and in vivo22. However, a systematic review on soursop’s anticancer properties proposed that further studies are required to verify the exact anticancer properties and the mechanism of action of its anticancer properties. More robust and systematic clinical trials are necessary to test and verify its true validity and safety before confirmed as a therapeutic anti-cancer agent22,23. Christia vespertilionis, commonly known as butterfly wing is an ornamental plant in cultivated gardens in South East Asia because of its uniquely shaped trifoliate leaves. In traditional medicine, this plant is believed to treat snake bites, tuberculosis, heal bone fractures, increase blood circulation, bronchitis and cold24. The extracts of Christia vespertilionis revealed antiproliferative and proapoptotic effects in all human medullary thyroid carcinoma (MTC) and human small intestinal neuroendocrine tumor (SI-NET) cell lines25. There was no comprehensive evidence concerning the phytochemistry, pharmacology and toxicology of this plant, and safety assessment and clinical trials were required before it can be integrated into the treatment of cancer26. Amygdalin is a cyanogenic glycoside plant compound found naturally in apricot kernels. It is also found in kernel of peaches and bitter almonds. Laetrile is a semi-synthetic form of amygdalin. The anti-cancer property of amygdalin is believed to come from the cyanide released from the enzymatic degradation of amygdalin27. Another theory claimed that cancers were due to the deficiency of a vitamin, named ‘vitamin B17’, which was the name given to amygdalin by a chemist E.T. Krebs28. Nevertheless, there was no reliable evidence supporting the alleged effects of laetrile for curative effects in cancer patients28,29. Yet, it had high risk of developing serious adverse effects from cyanide poisoning especially after oral ingestion of laetrile. Hence, the United States Food and Drugs Administration (FDA) and the European Commission had banned its use28. 83 Sabah snake grass (Clinacanthus nutans) has been traditionally used as natural medicine in Malaysia, Indonesia and Thailand for treating certain diseases such as skin rashes, insect bites, diabetes mellitus, fever and diuretics30. Phytochemical constituents of Clinacanthus nutans present in chloroform extract may be used as an alternate adjunctive or chemopreventive regimen for patients at risk of cancers as it possessed antioxidant and antiproliferative properties against cultured cancer cell lines31. An animal study found that Clinacanthus nutans possessed potential antitumour and immunomodulatory properties30. However, different ways of extraction may produce different cytotoxic activity. Hence, further studies were recommended on potential use of these extracts as anticancer and pharmaceutical applications32. The finding on reasons of using TCM in this study was supported by other studies, where most of the respondents used TCM to suppress the progression of cancer and improve physical well- 83 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 being33,34. TCM users believed that they are harmless and would do more “good” than “harm” to their general well-being35. TCM users are willing to try any form of therapy that could cure them or at least stabilise their life-threatening conditions. However, this is opposed by clinical practise as it may cause moderate to severe life threatening events and unknown possible side effects36. One of the reasons for delay in seeking treatment was the strong cultural belief in traditional medicine37. In a study done by Hisham & Yip in 2004 on 1,526 women with newly diagnosed breast cancer, about 45% presented at a late stage of the disease38. Delays in seeking conventional medical care had not only led to increased burden of the disease but also increased cost39. The results of this study conformed to a study done by Nagashekhara et al. in 2015 where increase in patient satisfaction with conventional treatment was correlated with a decrease in use of TCM5. Cancer patients that use TCM were often found among those not satisfied with conventional treatment due to side effects, worsening of symptoms or spreading of cancers40. In this study, there were 60.8% of TCM users that did not inform their doctors about their TCM usage. According to Farooqui et al. (2015), the major reason given for nondisclosure was “it is not important for the doctors to know about TCM use”, and this could indicate patients’ lack of knowledge regarding the harmful interactions of TCM with conventional therapies7. The main limitation of this study was that the subjects were interviewed at a hospital setting hence there was a possibility that patients were somewhat restrained in providing the complete account of their TCM use to please the interviewers. Patients may not admit that he or she is taking TCM simply due to the fear of being scolded by their doctors. Additionally, even though standardisation on the verbal delivery of the questionnaires in Malay and Mandarin was conducted before starting the data collection, some difficulties were still encountered by the interviewers in assisting the respondents to answer the questionnaire that was written in English.
Conclusion This study found that there was a high prevalence of TCM use among cancer patients and soursop, apricot seed, butterfly wing leaves and Sabah snake grass were the common types of TCM used. This finding further supported the claims that there is a growing interest in TCM use especially among cancer patients. Most of TCM users agreed that they used TCM to suppress the progression of cancer and they believed that TCM are able do so. On top of that, a significant difference was found between TCM users and non-TCM users in patient’s satisfaction level with conventional treatment and the delay in seeking conventional treatment. This issue should be raised to physicians and oncologists. Future studies may focus on the perceived benefits or adverse effects of TCM use on cancer progression, the amount of TCM used per patients and the costs incurred for TCM use.
Acknowledgement The authors would like to thank Madam Saidatul Raihan for her encouragement and guidance in conducting the study and the Director General of Health Malaysia for his permission to publish this 84 article. Our appreciations also go to all that had contributed to this study, especially to the participants whom had spent their valuable time in answering the questionnaires.
Conflict of Interest Statement No external funding was received and the authors declared no conflict of interest.
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25. Hofer, D.; Schwach, G.; Ghaffari-Tabrizi, N. Christia Vespertilionis Plant Extracts as Novel Antiproliferative Agent Against Human Neuroendocrine Tumor Cells. Oncol Rep. 2013, 29(1), 2219- 2226. 26. Dash, G.K. An Appraisal of Christia vespertilionis (L.F.) Bakh. F.: A Promising Medicinal Plant. International Journal of Pharmacognosy and Phytochemical Research. 2016, 8(6), 1037-1039. 27. Herbert, V. Laetrile: The Cult of Cyanide Promoting Poison for Profit. Am J Clin Nutr. 1979, 32(1), 1121-1158. 28. Milazzo, S.; Horneber, M. Laetrile Treatment for Cancer (Review). Cochrane Database Syst Rev. [Online] 2015; 1(4). http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD005476.pub4/pdf (Published online: Apr 18, 2015). 29. Milazzo, S.; Lejeune, S.; Ernst, E. Laetrile for Cancer: A Systematic Review of The Clinical Evidence. Supportive Care Cancer 2007, 15(6), 583-595. 30. Alam, A.; Ferdosh, S.; Ghafoor, K. Clinacanthusnutans: A Review of The Medicinal Uses, Pharmacology And Phytochemistry. Asian Pac J Trop Med.2016, 9(4), 402-409. 31. Yong, Y. K.; Tan, J. J.; Teh, S. S. Clinacanthusnutans Extracts are Antioxidant with Antiproliferative Effect on Cultured Human Cancer Cell Lines. Evid Based Complement Alternat Med. 2013, 13(1),1-8. 32. Sulaiman, I. S. C.; Basri, M.; Chan, K. W. In Vitro Antioxidant, Cytotoxic and Phytochemical Studies of Clinacanthusnutans Landau Lead Extracts. Afr JPharm Pharmacol. 2015; 9(34),861- 874. 33. Shaharudin, S. H.; Sulaiman, S.; Emran, N. A. The Use of Complementary and Alternative Medicine among Malay Breast Cancer Survivors. Altern Ther Health Med. 2011, 17(1), 50-56. 34. Molassiotis, A.; Fernadez-Ortega, P.; Pud, D. Use of Complementary and Alternative Medicine in Cancer Patients: A European survey. Ann Oncol. 2005, 16(4), 655-663. 35. Vivien, Y. W. C.; Er, A. C.; Mohd Noor, N. A. Chinese Culture and Cancer among Malaysian Chinese Cancer Survivors. Asian Social Science. 2013, 9(14), 30-41. 36. Niggemann, B.; Grüber, C. Side-effects of Complementary and Alternative Medicine. Allergy. 2003, 58(8), 707–716. 37. Khaw, K. W.; Ramli, N.; Rahmat, K. Ptosis due to Cavernous Sinus Syndrome as A Rare Presentation of Advanced Breast Metatstasis in Patient with Delayed Diagnosis. Malays Fam Physician. 2012, 7(1), 31-33. 38. Hisham, A. N.; Yip, C. H. Overview of Breast Cancer in Malaysian Women: A Problem with Late Diagnosis. Asian J Surg. 2004, 27(2), 130-3. 39. Knight, A.; Hwa, Y. S.; Hashim, H. Complementary Alternative Medicine Use amongst Breast Cancer Patients in the Northern Region of Peninsular Malaysia. Asian Pac J Cancer Prev. 2015, 16(8), 3125-3130. 40. Poonthananiwatkul, B.; Howard, R. L.; Williamson, E. M.; Lim, R. H. Cancer Patients Taking Herbal Medicines: A Review of Clinical Purposes, Associated Factors, and Perceptions of Benefit or Harm. J Ethnopharmacol. 2015, 175(1), 58-66.
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Comparing the Glycaemic and Weight Control Effects of Basal-bolus and Premixed
Insulin Regimen among Patients with Type 2 Diabetes Mellitus in Johor
Chong Men Yee1
1 Simpang Renggam Health Clinic, Kluang District Health Office, Johor State Health Department, Ministry of Health Malaysia
Abstract
Introduction: In Malaysia, conventional or human insulins are more commonly used than insulin analogues but studies comparing basal-bolus insulin regimen and premixed insulin regimen using conventional insulins are very limited. Objective: To compare the glycaemic and weight control effects of conventional basal-bolus and conventional premixed insulin regimens in patients with type 2 diabetes mellitus (T2DM) in Kluang District, Johor, Malaysia. Methods: A retrospective observational study was conducted on 122 T2DM adult patients in government primary health clinics in Kluang, Johor who received conventional insulin therapy. Patients were on either basal bolus or premixed insulin regimens. Changes in HbA1c, fasting blood sugar and body weight from baseline to the endpoint of study were recorded. Results: No significant differences (p > 0.05) in HbA1c, pre-breakfast and pre-bed fasting blood sugar and body weight changes were observed between patients with conventional basal-bolus insulin regimen and conventional pre-mixed insulin regimen. Basal-bolus insulin regimen significantly reduced pre-lunch and pre-dinner FBS compared to premixed insulin regimen. Conclusion: Basal-bolus conventional insulin regimen provides better control of pre-lunch and pre- dinner FBS. However, the decision of insulin regimens shall be based on clinical judgement of the healthcare providers and preference or compliance of the patients.
Keywords: type 2 diabetes mellitus, conventional insulin, premixed insulin, basal-bolus insulin, fasting blood sugar, HbA1c, weight control
NMRR ID: NMRR-16-1307-31592
Corresponding author: Chong Men Yee
Department of Pharmacy, 87 Simpang Renggam Health Clinic, Jalan Rambutan, Simpang Renggam, 86200 Kluang, Johor Email: [email protected]
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Introduction The main aim of diabetes mellitus treatment is to prevent complications by controlling blood glucose levels1. Findings from United Kingdom Prospective Diabetes Study (UKPDS) revealed that the Type 2 Diabetes mellitus (T2DM) patients usually lose half of their β-cell functions at the point of diagnosis, with a further annual decline of 5%2. The progressive β-cell destruction along with the course of the disease justifies the possible development of both basal and prandial insulin deficiency in T2DM patients3. Thus, insulin treatment, as one of the available options for such insulin deficiencies condition, can help to reduce blood glucose levels effectively and hence, improving glycaemic control1. Many patients of type I and type 2 diabetes mellitus would require insulin therapy to manage hyperglycaemia, particularly when insulin deficiency develops3. However, there is no consensus regarding the optimal regimen for insulin therapy3. Among various insulin regimens, basal-bolus insulin regimen is considered more closely mimicking the human physiological insulin secretions. A basal-bolus regimen generally involves three injections of rapid-acting insulin before each meal and one injection of long-acting insulin a day1,3. Attempts have been made to reduce the physical and mental burden associated with diabetes treatment such as fear over frequent insulin injections required by basal-bolus therapy, risk of hypoglycaemia, weight gain and lifestyle restrictions1,3, with the use of premixed insulin. Several studies using analogue insulins have shown that twice-daily injections of pre-mixed insulin therapy resulted in comparable percentage of HbA1c reduction comparing to basal-bolus therapy, but requiring fewer injections1.This offers a convenient alternative to the basal-bolus therapy for T2DM patients requiring insulin therapy. The use of conventional insulin (also known as human insulin) supersedes the use of analogue insulin in the public primary healthcare clinics in Malaysia. This may be due to the lower price of conventional insulin compared to insulin analogues. To date, many studies have evaluated and compared the glycaemic and weight control in patients receiving analogue basal-bolus and analogue premixed insulin regimes. Nevertheless, similar studies comparing conventional basal-bolus and premixed insulin regimens are very limited. Considering the lower cost of conventional insulin and its more common use in the local setting, evaluating the effectiveness of basal-bolus and premixed regimen using conventional insulin is necessary. This information is important to help healthcare providers in choosing the more favourable insulin regimen for the patients. Therefore, this study was carried out to compare the glycaemic and weight control effects of conventional basal-bolus and conventional premixed insulin regimes in patients with T2DM in Kluang District, Johor, Malaysia.
Methods Study design and sampling This research was registered on the Malaysian National Medical Research Register (NMRR) (ID NMRR-16-1301-31592) and approved by the Medical Research Ethical Committee (MREC) of Ministry of Health Malaysia. This retrospective study was conducted in all government primary health care 88 clinics in Kluang District, Johor between 1 Jan 2016 to 31 Dec 2016. Data was collected from patients’ medical records in the outpatient diabetic clinics. Inclusion criteria were: patients diagnosed with T2DM with a period of more than 12 months, aged 18 years and above, HbA1c value above 7.5%, on a stable conventional insulin therapy for at least 3 months (no change in treatment / regimen and less than 30% change in dosage), and on either basal-bolus or premixed insulin regimens. In this study, patients diagnosed with type 1 diabetes mellitus (T1DM), had switched insulin regimen at any time in between baseline to endpoint, and with incomplete medical record within the one-year study period were excluded. In addition, patients who experienced severe hypoglycaemia episodes within the last 3 months, impaired hepatic functions, and active proliferative diabetic retinopathy 6 months prior to screening were also excluded.
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Power and Sample Size Calculation software version 3.0.43 by Dupont & Plummer (2003) was used to calculate the sample size. A minimum sample size of 61 patients were needed in each group to achieve a power of 80% to detect an absolute difference of 0.4% in HbA1c reduction between the groups (standard deviation of 1.1%, two-sided α = 0.05 and β = 0.2) in order to obtain statistical significance in this study. Data extracted from patients’ medical records in outpatient diabetic clinics were: demographic information (age, race, gender, ethnicity, weight, duration of years with diabetes), medication regimens (conventional basal-bolus or conventional premixed insulin), laboratory parameters (HbA1c and fasting blood sugar (FBS)), and doctor’s interventions. Data were recorded in a data collection form prior to data entry and statistical analysis.
Statistical analysis Using SPSS version 18.0, data processing and statistical analyses were conducted. Characteristics of the patients were analysed and presented as descriptive statistics (e.g. mean and standard deviation and frequency as well as percentage and proportions). Prior to conducting inferential statistics, the data were examined using Kolmogorov-Smirnov and Shapiro-Wilk tests for ascertaining normality. Independent sample t-test was carried out to compare two groups (Basal-bolus Insulin Regimen and Premixed Insulin Regimen) based on their mean changes of HbA1c and FBS from baseline to endpoint. Level of significance of 0.05 was used for assigning any statistical significance.
Results A total of 122 patients fulfilled the inclusion criteria and were included in the study, with 61 patients in each group (Basal-bolus Insulin Regimen and Premixed Insulin Regimen). The demographics and baseline characteristics of the patients were comparable (p>0.05) (Table 1). Both groups of patients had similar mean age (around 59 years old) and mean duration of T2DM history (around 12 years). In addition, both groups had similar baseline HbA1c, FBS levels, baseline weight and comparable incidence of co-existing diabetes-related disorders. All patients received same brand of human insulins manufactured by Sanofi-Aventis Deutschland GmbH, Germany. In the Basal-bolus Insulin Regimen group, patients received Insuman Basal (long acting human insulin) as pre-bed basal dose, and Insuman Rapid (rapid-acting human insulin) as pre-prandial doses, while all patients in the Premixed Insulin Regimen group received Insuman Comb, which is a biphasic isophane insulin suspension consisting of 25% dissolved insulin and 75% crystalline protamine insulin.
Table 1: Demographics and baseline characteristics of the study population Characteristics* Basal-bolus (n=61) Premixed (n=61) Gender, n (%) Male 24 (39.3) 31 (50.8) Female 37 (60.7) 30 (49.2) 89 Age, mean (SD) 57.82 (10.6) 58.95 (8.8) Duration of diabetes (years), mean (SD) 11.93 (6.1) 12.06 (5.9) Race, n (%) Malay 51 (83.6%) 50 (82%) Chinese 7 (11.5%) 8 (13.1%) Indian 3 (4.9%) 3 (4.9%) *Levene’s test for homogeneity-of-variance (p>0.05); SD – standard deviation
Changes in HbA1c, FBS and body weight throughout the course of the study at baseline and endpoint were shown in Table 2. The difference in mean HbA1c reduction between Basal-bolus regimen and Premixed regimen in the study population was not statistically significant. Likewise, there 89 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 were no significant differences between the two groups in pre-breakfast and pre-bed FBS baseline-to- endpoint changes. Nevertheless, the baseline-to-endpoint changes in pre-lunch and pre-dinner FBS were significantly different. On the other hand, the mean changes in body weight in both groups were not statistically different.
Table 2: HbA1c and FBS concentrations at baseline and endpoint Basal-bolus Premixed (n=61), Variables (n=61), mean p-value mean (SD) (SD) HbA1c (%) Baseline 11.65 (2.30) 10.98 (2.40) Endpoint 10.85 (2.09) 11.05 (2.53) Mean HbA1c difference -0.8048 (2.51) 0.0682 (3.00) p=0.084 Adjusted mean difference in HbA1c change -0.873 (-1.866, 0.1206) between groups, % (95% CI) Pre-breakfast FBS (mmol/l) Baseline 11.82 (5.75) 14.03 (15.60) Endpoint 11.39 (5.48) 11.15 (3.76) Baseline-to-endpoint change -0.43 (0.86) -2.89 (15.68) p=0.263 Pre-lunch FBS (mmol/l) Baseline 16.63(21.78) 12.10 (4.75) Endpoint 12.59 (5.29) 13.02 (5.00) Baseline-to-endpoint change -4.04 (2.32) 0.92 (3.92) p=0.038* Pre-dinner FBS (mmol/l) Baseline 12.61 (5.71) 12.05 (4.72) Endpoint 11.56 (4.42) 13.52 (5.82) Baseline-to-endpoint change -1.05 (3.75) 1.48 (4.02) p=0.001* Pre-bed FBS (mmol/l) Baseline 11.32 (5.39) 12.07 (5.09) Endpoint 11.73 (5.44) 13.14 (5.06) Baseline-to-endpoint change 0.41 (0.68) 1.06 (3.53) p=0.429 Weight (kg) Baseline 71.06 (17.68) 73.49 (16.27) Endpoint 71.68 (14.89) 73.02 (26.13) Baseline-to-endpoint change 0.62 (3.37) -0.47 (5.52) p=0.190 * the difference between the two groups was statistically significant
Discussion Type 2 diabetes mellitus (T2DM) is a chronic disease with progressive loss of beta-cell function3. This means that most patients with long-standing T2DM may ultimately require insulin therapy alongside 90 oral antidiabetics to achieve optimal glycaemic control (HbA1c ≤ 6.5%). The targeted HbA1c level may not be achieved due to non-compliance with the prescribed insulin regimen, especially with the concurrent issue of polypharmacy. Thus, it is essential to provide an effective, safe and flexible insulin regimen to maximise the effect of insulin therapy. Clinical trials (e.g. PREFER study4), systematic review5 and economic evaluation6 had shown that insulin treatment with basal-bolus regimen was superior in the overall glycaemic control compared to premixed insulin. In line with the findings of previous studies, our study showed that the basal-bolus regimen reduced mean HbA1c from baseline to endpoint while premixed showed a slightly increase of HbA1c in the study populations. However, the difference between the mean decrease in HbA1c in the two groups [-0.8048% (SD 2.51) versus 0.0682% (SD 3.00)] was not statistically significat (p>0.05).
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The result supported the LanScape study7, which concluded that basal-bolus regimen was non-inferior to biphasic insulin twice daily in term of HbA1c reduction. In addition, we observed no significant differences between groups in pre-breakfast and pre- bed FBS concentration. Nevertheless, the pre-lunch and pre-dinner FBS of patients with basal-bolus regimen were reduced compare to premixed regimen in which the FBS of patients were slightly increased. These results were similar to the findings by Yamada et al. (2013) which suggested that basal-bolus regimen achieves better glucose profiles than premixed insulin therapy in T2DM patients, particularly after lunch8. However, the basal-bolus approach usually requires once daily subcutaneous administration of basal insulin in combination with three pre-prandial or corrective doses of rapid- acting insulin. The complexity of this approach may limit its acceptance among T2DM patients especially when compared to the premixed insulin regimen which usually only requires two subcutaneous injections per day. Another important consideration when selecting a treatment for diabetes is the effect on body weight. Medications-induce weight gain is undesirable in diabetes given that majority of T2DM patients are already obese or overweight, and obesity is a risk factor for diabetes and cardiovascular diseases. There was, however, a slight weight gain in the basal-bolus group comparing to slight weight lost in the premixed insulin group, although difference in baseline-to-endpoint weight changes between the two groups were not statistically significant. This result was comparable with the randomised pragmatic trial6 conducted using insulin analogue, which also showed that patients with basal-bolus regimen had higher weight gain than the premixed regimen at its follow-up. There are several limitations in the study. We acknowledged that our study sample size was small and was a retrospective observational in design which could limit the generalisation of the findings. As all information were extracted from patients’ medical records, there may be errors due to the absence of information or incorrect information in the records. Furthermore, this study was not able to capture adverse events reports such as the frequency of hypoglycaemia, allergic reactions and cardiovascular events. Discontinuations or deaths due to insulin treatment during the study period was not detected. Also, patients with acute or chronic kidney failure was not excluded as majority of the patients with renal impairment were on basal-bolus, eliminating them will result in lack of subjects. In addition, there were lack of information on patients’ compliance to insulin administration, insulin injection technique and diets, which were important factors affecting diabetic control in the primary care setting. Furthermore, the greatest limitation of study was the 12-month duration from baseline to endpoint for the measurement of HbA1c changes instead of 3 months, due to cost limitations of laboratory tests the non-interventional design of the study. These might affect the quality of the data. It is recommended that future studies should compare the safety and cost-effectiveness of basal-bolus and premixed insulin regimens in T2DM patients in the primary care settings. Also, large-sized prospective clinical trials with more frequent HbA1c and FBS monitoring are needed to confirm the findings of our study. 91 Conclusion In summary, there were no significant differences in HbA1c reductions, pre-breakfast and pre-bed FBS changes and weight changes between conventional basal-bolus and conventional premixed insulin regimens, while basal-bolus insulin regimen significantly reduced pre-lunch and pre-dinner FBS compared to premixed insulin regimen. Since basal-bolus conventional insulin regimen provide better control of pre-lunch and pre-dinner FBS, it may be indicated for patients who require better control FBS. Nevertheless, the decision of insulin regimens shall be based on clinical judgement of the healthcare providers and preference or compliance of the patients.
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Acknowledgement The author would like to thank the Director General of Health Malaysia for his permission to publish this article .
Conflict of Interest Statement No external funding was received and the authors declared no conflict of interest.
References 1. Satoru Y.; Ryo H.; Gaku I.; Yoshifumi Y.; Junichiro I.; Koichiro A.; et al. Comparison of glycemic variability between basal-bolus and premixed insulin therapy. Journal of Diabetes Mellitus 2013, 3(2). http://file.scirp.org/pdf/JDM_2013050916105529.pdf (accessed June 19, 2016). 2. Nazia I.P.; Noordin O.; Nor Ilyani M.N.; Nik Nur Fatnoon N. A.. Safety of basal-bolus versus premixed insulin intensification regimens in the management of type 2 diabetes mellitus: A narrative review of a 14-year experience. Journal of Taibah University Medical Sciences 2013, 10(23). http://www.sciencedirect.com/science/article/pii/S165836121500075X (accessed June 19, 2016). 3. Fritsche A.; Larbig M.; Owens D.; Haring H.U. Comparison between a basal-bolus and a premixed insulin regimen in individuals with type 2 diabetes–results of the GINGER study. Diabetes, Obesity and Metabolism 2010, 12. http://onlinelibrary.wiley.com/doi/10.1111/j.1463- 1326.2009.01165.x/epdf (accessed June 19, 2016). 4. Liebl A., et al. Comparison Of Insulin Analogue Regimens In People With Type 2 Diabetes Mellitus In The PREFER Study: A Randomized Controlled Trial. Diabetes Obes Metab 2009, 11(1), 45-52, https://www.ncbi.nlm.nih.gov/pubmed/18643839 (accessed June 26, 2016). 5. Ilag L.L., et al. Prandial Premixed Insulin Analogue Regimens Versus Basal Insulin Analogue Regimens In The Management Of Type 2 Diabetes: An Evidence-Based Comparison. Clinical Therapeutics 2007, 29, 1254-1270. https://www.ncbi.nlm.nih.gov/pubmed/18036388 (accessed June 30, 2016). 6. Levin P.A., et al. Glycemic Control With Insulin Glargine Plus Insulin Glulisine Versus Premixed Insulin Analogues In Real-World Practices: A Cost-Effectiveness Study With A Randomized Pragmatic Trial Design. Clinical Therapeutics 2011, 33 (7), 841-850. https://www.ncbi.nlm. nih.gov/pubmed/21719107 (accessed June 30, 2016). 7. Vora J., et al. Intensifying Insulin Regimen After Basal Insulin Optimization In Adults With Type 2 Diabetes: A 24-Week, Randomized, Open-Label Trial Comparing Insulin Glargine Plus Insulin Glulisine With Biphasic Insulin Aspart (Lanscape). Diabetes Obes Metab 2015, 17 (12), 1133- 1141. https://www.ncbi.nlm.nih.gov/pubmed/26085028 (accessed June 26, 2016). 8. Yamada S., et al. Comparison Of Glycemic Variability Between Basal-Bolus And Premixed Insulin Therapy. Journal of Diabetes Mellitus 2013, 3 (2), 45-51, www.scirp.org/journal/ Paper Information.aspx?paperID=31104 (accessed June 26, 2016). 92
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Patients’ Beliefs about Generic Medicines in the Outpatient Setting, Sibu Hospital
Chuo Sing Hong1, Carmen Wong Jia Jia1, Ling Mei Siew1, Sia Khang Lin1, Tiong Chang Hwa1
1 Sibu Hospital, Ministry of Health Malaysia
Abstract
Introduction: Malaysia implemented National Generic Medicines policy since 2006 to encourage generic medicines prescribing. After ten years of implementation, patients’ belief about generic medicines is yet to be assessed. Objective: The objectives were to assess patients' beliefs about the similarity and efficacy of generic medicines, and to determine the association between demographic characteristics with patients’ beliefs about the generic medicines in Sibu Hospital. Methods: This is a cross-sectional study conducted at the outpatient pharmacy of Sibu Hospital between January and May 2017 using convenience sampling method. The Generic Medicine Scale (GMS), a validated self-administered questionnaire was used. Data was analysed using SPSS software. Results: A total of 150 respondents were included in the analysis. Majority of the respondents knew about generic medicines (60.7%). The mean scores of the efficacy and similarity domains were 2.97 (95% CI 2.89, 3.04) and 3.18 (95% CI 3.08, 3.28) respectively. In terms of efficacy, 41.3% of the respondents believed that generic medicines were as efficacious as branded medicines and could be used to treat the same illnesses (54.0%), but 44.7% of respondents believed that generic medicines took longer time to be efficacious and longer treatment duration was required (43.3%). With regard to similarity, majority of respondents were neutral about generic medicines being similar to branded medicines, but 60% of the respondents agreed that generics had different box (packaging). Respondents’ beliefs on generic medicines was significantly affected by age (p=0.001), gender (p=0.007), ethnicity (p=0.014), education level (p=0.028) and knowledge on generic medicines (p=0.036). Conclusion: Patients attending the outpatient pharmacy in Sibu Hospital had mixed belief on the efficacy of generic medicines, and were relatively neutral on the similarities of generic drugs compared to branded product. Age, gender, ethnicity and education level were shown to be affecting respondents’ perception on generic medicines.
Keywords: generic medicines, Sibu Hospital
93 NMRR ID: NMRR-16-1967-32973
Corresponding author: Chuo Sing Hong Department of Pharmacy, Hospital Sibu, Batu 5 ½, Jalan Oya Lama, 96000 Sibu, Sarawak Email: [email protected]
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Introduction Generic medicine is medicine that is similar to the innovator medicine in terms of its dosage form, safety, strength, route of administration, quality, performance characteristics and intended use. It is proven to be bioequivalent to innovator medicine. In order for a generic medicine to be marketed, pharmaceutical companies must get approval from the national authority by submitting an abbreviated new drug application (ANDA). In Malaysia, the National Pharmaceutical Regulatory Agency is the regulatory body that issues approval for generic medications. The criteria for generic medicines to gain approval are the generic medicines must contain the same active ingredients, strength, dosage form and route of administration as the innovator medicine. The indications of the generic medicine must be identical and proven to be bioequivalent to the innovator medicine. The manufacturing of generic medicines must meet the same batch requirements for the formulation in terms of its identity, strength, purity and quality. By meeting the requirements, health professional and consumers can be assured that generic medicines are as effective as innovator medicines1. Healthcare expenditure is increasing globally over the years. Pharmaceutical cost has been shown to be the second driver for healthcare cost escalation, after healthcare professional wages. A similar trend is observed in the Malaysian healthcare system. In Malaysia, the public sector caters for approximately 65% of the Malaysian population2. Public healthcare services are comprehensively subsidised by the Malaysian government. National surveys have demonstrated the progressive cost escalation in pharmaceutical industry2. A report by the World Health Organization (WHO) stated that healthcare expenditure in Malaysia is significantly higher than the average value of other upper-middle income countries. One of the approaches to reduce healthcare expenditure is encouraging the use of generic medicines instead of expensive innovator medicines. In Malaysia, generic medicines substitution is reported to potentially save up to 60% of the pharmaceutical cost1,3. Due to the cost saving benefits of generic medicines substitution, Malaysian government has formulated policies to encourage the use of generic medicines. Generic Medicines Policy formulated under the third component of Malaysian National Medicines Policy (2007) encourages generic prescribing and substitution to reduce the pharmaceutical expenditure2. Despite continuous effort by the Malaysian government to increase generic substitution rate in Malaysia, generic medicines only contributes to about 40% of the total prescription market3. Factors that contribute to low generic medicines market are misconception and insufficient knowledge of consumers or patients about generic medicines3. Generic medicines are cheaper compared to innovator medicines, ideally. Yet consumers always have the perception that cheaper in price means lower in quality. It was found that one-third of patients assumed that generic drugs are cheaper because they are less efficacious1,3. However, this perception is not entirely true. Generic medicines are cheaper because pharmaceutical companies do not have to repeat the costly clinical trials of new drugs and do not pay for the costly advertising, marketing and promotion. Moreover, market competition among multiple generic companies that market the same generic products usually result in lower prices1. 94 A national wide study conducted in the United States by Shrank et al. found that Americans generally agreed that generic medicine was less expensive and had better value than innovator medicine. Although patients believed that generic medicine was just as good as innovator drug, only one-third of Americans agreed to use generic medicine. The study also indicated that wealthier patient preferred generic medications while healthier patients were more concerned with the safety and efficacy of generic drugs6. On the other hand, the perception of Jordanian patients towards generic drug substitution was excellent. According to Farris et al., 92% of Jordanian patients preferred to be prescribed the cheapest medicine. They believed that cost should be considered before medication was prescribed. Besides that, 78% of the patients agreed that generic substitution could provide significant cost saving. The study also showed that 83% of Jordanian believed that cost of medicines in Jordan was the main driver to choose generic medicines7. 94 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018
Another review conducted by Hakonsen et al. in Norway was aimed to summarise the patient’s perspectives on generic substitution in the western world between 2000 and 2011. The outcomes of the review showed that one third of all patients still preferred to use brand named medicines. Some patients reported to experience more adverse effects with generic medicines and claimed that generic medicines were less efficacious compared to innovator medicines. The authors concluded that poor awareness on generic substitution caused confusion and reduced patient acceptability to generic medicines. Also, patient’s acceptance of generic substitution was influenced by age, level of education, diseases’ perception, generic drug information and prescribers’ advice8. In Malaysia, two studies were conducted to explore the perception of generic medicines substitution after the implementation of generic medicines policy in year 2006. The first study conducted by Thomas et al. showed that more than half (67.5%) of the consumers in community pharmacies did not know what generic medicines were10. Among the consumers who never use generic medicines, they perceived that generic medicines were not as effective or as safe as brand medicines. Price was one of the reasons why consumers chose to use generic medicines, in 31 out of 86 respondents. A lack of knowledge about generic medicines was also the factor that led to negative perception amongst the consumers in community pharmacy setting in Malaysia. The second study conducted by Wong et al. in a government hospital showed that only 49% of patients involved knew the term ‘generic medicine’9. Almost half of the patients had negative belief in generic medicines. Few demographic characteristics were found to significantly affect patient’s belief on generic medicines. Patient with higher level of education and income status tended to have positive belief on generic medicines3. As part of the implementation of National Generic Medicines Policy, Sibu Hospital had been supplying more and more generic medicines to patients since year 2006. After more than 10 years of utilising generic medicines, we would like to explore the patients’ beliefs and views about generic medicines. To the best of our knowledge, there is no similar study conducted regarding perception of using generic medicines among the Sarawak population. Therefore, this study aimed to assess the current beliefs and views of patients on generic medicines in Sibu Hospital. The objectives of our study were (1) to assess patients' beliefs about the similarity and efficacy of generic medicines, and (2) to determine the association between demographic characteristics with patients’ beliefs about the generic medicines in Sibu Hospital.
Methods This was a cross-sectional study conducted at the outpatient pharmacy, Sibu Hospital, from 1 January to 31 March 2017. A validated self-administered Generic Medicines Scale (GMS) questionnaire in both Malay and English language was used as the data collection tool. The inclusion criteria were any adult patients aged more than 18 years old, who were able to speak, read and write in Malay or English language. Meanwhile, paediatric patients, caregivers, psychiatric patients and patients with cognitive impairment were excluded. Convenient sampling method was applied in the study. Every patient that 95 fulfilled the eligibility criteria was approached by the investigators. Patients agreed to participate in the research were given a letter explaining the background, purpose and procedure of the study. A brief explanation on definition of generic and original medicine was given to the respondents. Patients who consented to participate were given the questionnaire to be filled in. Sibu Hospital is the major specialist referral hospital for the central region of Sarawak. The average number of patients attending outpatient pharmacy in Sibu Hospital per day was 650. Over the three-month data collection period, total estimated number of patients was 58,500. Sample size was calculated using Sample Size Calculator for Estimations Version 1.0.03 developed by Lin Naing et al.11. By using the estimated population of 58,500 patients in the outpatient pharmacy, with confidence level of 95% and acceptable margin error (precision) of 5% and standard deviation of 0.33, the
95 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 calculated sample size was 139. However, to allow for potentially high non-response rate, the final sample size was increased by 20% to 170. Generic Medicine Scale (GMS) questionnaire developed by Figueirras et al.12 was used to assess patients’ beliefs about generic medicines. The English version of the GMS was validated by Figueirras et al. while the Malay version of the GMS was validated by Wong et al. in 201413. Both versions of the questionnaire were used in this study. The GMS consisted of two parts: Part A was collecting respondents’ social demographic information (age, gender, ethnic, education level and monthly income), while Part B was questions relating to respondents’ knowledge and perceptions on generic medicines. Part B consisted of a combination of 16 positive and negative statements using five points Likert scale (1=strongly disagree, 2=disagree, 3=neutral, 4=agree and 5=strongly agree). Respondents were expected to spend approximately 15 to 20 minutes to complete the questionnaire. The data was analysed using Statistical Package for Social Sciences (SPSS). Descriptive statistics were used to describe the demographic data of the participants. The GMS questionnaire was presented as descriptive data in numbers and percentage as well as mean score and 95% confidence interval (CI) for the efficacy and similarity domains. Negative statements in the efficacy domain was re- coded during analysis so that the score can reflect same direction in respondents’ beliefs. The mean score calculated ranged from one (negative beliefs) to five (positive beliefs) with three as the neutral point. Independent t-test was used to detect the significant difference in participants’ response between genders and knowledge about generic medicines. One-way Anova was used to detect the significant differences in participants’ response for other demographic factors, namely ethnic, age, education level, income and occupation of respondents. Post-hoc analysis was applied to determine significant differences between groups for factor with more than two levels, by using Scheffé method. All these tests were performed with significance level set at 0.05.
Results A total of 332 patients were approached during the study period and 158 patients were consented to participate in this study, which led to the low response rate of 47.6%. Eight out of the 158 patients were excluded from the analysis due to more than 70% missing data in the questionnaire. This resulted the final number of respondents at 150. The respondents’ demographic characteristics were shown in Table 1. The mean age of the final respondents was 42.7 years old (standard deviation 15.86). Majority of the respondents were female (56.7%), Chinese (52.0%), had at least secondary education (48.7%) and from lower income group earning less than RM1,000 a month (44.7%). More than half (60.7%) of the respondents knew about generic medicines. Table 2 and Table 3 showed the responses for the efficacy and similarity domains. The mean score of efficacy domain was 2.97 (95% CI 2.89, 3.04) while the mean score for similarity domain was 3.18 (95% CI 3.08, 3.28). Almost half (41.3%) of the respondents believed that efficacy of generic medicines were the same as branded medicines and it could be used to treat the same illnesses (54.0%). However, almost half of the patients believed that generic medicines took longer time to be 96 effective (44.7%), required longer treatment duration (43.3%), should be used for less serious illnesses (53.3%) and cheaper because of reduced efficacy (34.0%). In terms of quality, 41.4% of the respondents disagreed that generic medicines were made with lower quality substances but 36.6% respondents disagreed that the quality control of generic medicine was better. In terms of patients’ beliefs on the similarities of generic medicines, majority of the respondents were neutral on the similarities of tablet (36.0%), taste (44.0%) and side effects profile (42.7%) of generic medicines compared to branded medicines. However, more than half of the respondents knew generic medicines had different box (60.0%) and usage is similar to branded medicines (50.7%). Table 4 showed the factors influencing patients’ beliefs about the generic medicines. The respondents’ beliefs on generic medicines was significantly affected by age (p=0.001), gender (p=0.007), ethnic (p=0.014), education level (p=0.028) and knowledge on generic medicines 96 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018
(p=0.036). Male agreed treatment with generic antibiotics were less efficacious compared to branded antibiotics (p=0.021). Those who knew about generic medicines agreed that generic medicines were used for the same illnesses (p=0.036). Compared to Malays, Chinese were more prone to believe that generic medicines took longer treatment duration (p=0.021), have better quality control (p=0.001) and generic medicines had a different box compared to branded medicines (p=0.038). Malays were more prone to believe that generic medicines were the same as branded medicines compared to Sarawak Bumiputeras (p=0.023). Age was found to affect respondents’ belief in generic medicines too. Results showed only respondents between 31 and 40 years old had higher level of agreement that generic medicines had similar taste as branded medicines compared to respondents more than 50 years old. In terms of education level, degree holders (p=0.027) believed that generic medicines had the same effect as brand medicine compared to respondents with primary education only.
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Table 1: Patients’ demographic characteristics (N= 150) Characteristics n (%) Gender Male 65 (43.3) Female 85 (56.7) Ethnic Chinese 78 (52.0) Sarawak Bumiputera 54 (36.0) Malay 18 (12.0) Age group ≤ 30 40 (26.7) 31-40 31 (20.7) 41-50 29 (19.3) 51-60 26 (17.3) > 60 24 (16.0) Education No formal education 6 (4.0) Primary education 17 (11.3) Secondary education 73 (48.7) Form 6 and diploma 31 (20.7) Degree and above 23 (15.3) Income < RM1,000 67 (44.7) RM1,000 - RM2,000 32 (21.3) RM2,001 - RM3,000 22 (14.7) RM3,001 - RM4,000 14 (9.3) > RM4,000 11 (7.3) Missing data 4 (2.7) Occupation Professional 28 (18.7) Non-professional 50 (33.3) Self-employed 17 (11.3) Unemployed 50 (33.3) Missing data 5 (3.3) Ask doctor about medications
Yes 100 (66.7) 98 No 50 (33.3) Having medical cards for health insurance Yes 69 (46.0) No 81 (54.0) Know about generic medicine Yes 91 (60.7) No 59 (39.3)
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Table 2: Patients’ beliefs about the efficacy of generic medicines (n=150) Number of responses, n (%) Items in questionnaire Strongly Strongly Disagree Neutral Agree disagree agree 1. The efficacy of generic medicines is same as that of the brand 6 (4.0) 45 (30.0) 37 (24.7) 57 (38.0) 5 (3.3) medicines. 2. Generic medicines take longer time to be efficacious. 4 (2.7) 31 (20.7) 48 (32.0) 63 (42.0) 4 (2.7) 3. Generic medicines are good for less serious diseases. 5 (3.3) 27 (18.0) 38 (25.3) 75 (50.0) 5 (3.3) 4. Treatments with generic medicines take longer time. 4 (2.7) 33 (22.0) 48 (32.0) 60 (40.0) 5 (3.3) 5. Generic medicines are made with lower quality substances. 4 (2.7) 58 (38.7) 43 (28.7) 39 (26.0) 6 (4.0) 6. Generic antibiotics are less efficacious than brand antibiotics. 4 (2.7) 33 (22.0) 60 (40.0) 45 (30.0) 8 (5.3) 7. Generic medicines have a better quality control than brand 2 (1.3) 53 (35.3) 52 (34.7) 39 (26.0) 4 (2.7) medicines. 8. Generic medicines are cheaper because they are less 0 (0.0) 62 (41.3) 37 (24.7) 46 (30.7) 5 (3.3) efficacious. 9. Generic medicines have the same effect than brand ones. 2 (1.3) 45 (30.0) 48 (32.0) 52 (34.7) 3 (2.0) 10. Generic medicines are used for the same illnesses. 2 (1.3) 20 (13.3) 47 (31.3) 76 (50.7) 5 (3.3)
Table 3: Patients' beliefs about the similarities of generic medicines (n=150) Number of responses, n (%) Items in questionnaire Strongly Strongly Disagree Neutral Agree disagree agree 11. Generic tablets are the same as brand ones. 1 (0.7) 44 (29.3) 54 (36.0) 48 (32.0) 3 (2.0) 12. Generic medicines have a similar taste as brand medicines. 2 (1.3) 38 (25.3) 66 (44.0) 42 (28.0) 2 (1.3) 13. Generic medicines have the same side effects as brand 2 (1.3) 36 (24.0) 64 (42.7) 46 (30.7) 2 (1.3) medicines. 14. Generic medicines have a different box from brand medicines. 2 (1.3) 16 (10.7) 42 (28.0) 81 (54.0) 9 (6.0) 15. The use of generic medicines is similar to brand ones. 5 (3.3) 25 (16.7) 44 (29.3) 66 (44.0) 10 (6.7) 16. Generic medicines are exactly the same as brand medicines. 6 (4.0) 40 (26.7) 47 (31.3) 49 (32.7) 8 (5.3)
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Table 4: Factors affecting patients’ beliefs about the generic medicine in Sibu Hospital and significant level (p-value) Education Know Items in questionnaire Gender* Ethnic** Age** Income** Job** level** generic* 1. The efficacy of generic medicines is same as that of the 0.524 0.685 0.032p 0.363 0.526 0.262 0.451 brand medicines. 2. Generic medicines take longer time to be efficacious. 0.310 0.349 0.178 0.063 0.456 0.727 0.437 3. Generic medicines are good for less serious diseases. 0.952 0.836 0.452 0.156 0.194 0.922 0.805 4. Treatments with generic medicines take longer time. 0.211 0.011p 0.301 0.837 0.744 0.451 0.190 5. Generic medicines are made with lower quality 0.125 0.268 0.669 0.184 0.335 0.574 0.149 substances. 6. Generic antibiotics are less efficacious than brand 0.021 0.887 0.278 0.266 0.411 0.934 0.231 antibiotics. 7. Generic medicines have a better quality control than brand 0.231 0.001p 0.133 0.108 0.074 0.959 0.124 medicines. 8. Generic medicines are cheaper because they are less 0.706 0.084 0.428 0.648 0.292 0.496 0.599 efficacious. 9. Generic medicines have the same effect than brand ones. 0.892 0.040p 0.027p 0.004p 0.696 0.328 0.726 10. Generic medicines are used for the same illnesses. 0.602 0.284 0.195 0.024p 0.788 0.780 0.036 11. Generic tablets are the same as brand ones. 0.562 0.011p 0.052p 0.174 0.437 0.476 0.739 12. Generic medicines have a similar taste as brand 0.200 0.099 <0.0001p 0.040p 0.521 0.140 0.285 medicines. 13. Generic medicines have the same side effects as brand 0.342 0.303 0.088 0.024p 0.500 0.703 0.797 medicines. 14. Generic medicines have a different box from brand 0.129 0.034p 0.140 0.115 0.591 0.915 0.632 medicines. 15. The use of generic medicines is similar to brand ones. 0.524 0.372 0.006p 0.011p 0.804 0.906 0.681 16. Generic medicines are exactly the same as brand 0.927 0.231 0.171 0.355 0.806 0.461 0.500 medicines. All data were normally distributed, tested with Kolmogorov-Smirnov test. * Independent t-test, ** One-way Anova, p Post-Hoc using Scheffe method
100 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 Discussion The implementation of generic medicines policy is necessary to reduce the government’s financial burden in the heavily subsidised healthcare system in Malaysia. Year 2017 marked the first decade Malaysia implemented generic medicines policy. The findings from this study could serve as a review of general public’s acceptance and confidence in generic medicines policy. Our study showed 60.7% of the respondents knew about generic medicines, which was higher compared to the findings of 28.3% by Al-Gegadi et al.15 in Penang, 32.5% by Thomas and Vitry4 in Kuala Lumpur and 49% by Wong et al.3 in Alor Setar. This finding reflects the steadily increasing trend of awareness towards generic medicines over the years compared to study3,4,15 done during the early implementation of generic medicines policy. Despite the knowledge on generic medicines, our respondents showed mixed beliefs in generic medicines. This finding was similar to study done by Wong et al.5 Almost half of our respondents showed negative perception on efficacy of generic medicines, for example it took longer time to be effective (44.4%), required longer treatment duration (43.3%), should be used for less serious illnesses (53.3%) and generic medicines were cheaper because of reduced efficacy (41.3%). This could imply that respondents may not have the confidence to use generic medicines for serious or life threatening disease. We would also like to highlight that almost one third of the respondents were neutral in their belief on the efficacy of generic drugs. This could reflect that the respondents were unsure whether there is a difference between generic and branded drugs. In terms of quality control, respondents were also showing conflicting opinions. Almost half (41.4%) of the respondents disagreed that generic medicines were of lower quality but 36.6% respondents disagreed that the quality control of generic medicine was better. General public might be rarely exposed to the quality assurance process and strict compliance to Good Manufacturing Practice required in any pharmaceutical manufacturing plant. The national generic drug recall notification on atenolol tablet in January 2017 that coincided with data collection period, could have affected the general public’s confidence in quality control. Therefore, it is important to empower patient with information about regulatory approval and registration system for medicines in the country to boost their confidence in the quality of generic medicines. Majority of the respondents were neutral on the similarities of tablets (36.0%), taste (44.0%), side effects profile (42.7%) of generic medicines compared to branded medicines. This may be due to lack of knowledge about the similarity and difference between generic and original medicines. However, more than half of respondents knew generic medicines had different box (60%) and usage is similar to branded medicines (50.7%). This could be related to their experience with brand switching during medication supply in the pharmacy. Whenever there is any brand switching, changes in the packaging would first catch the eyes of the patients while staff at dispensing counter would explain to the patients about the brand switching and the similarity in the drug efficacy. However, patients may not routinely compare the differences in the taste and side effects profiles between generic medicines and branded medications. We also found out that majority of respondents in the less than 30 years old 101 group were neutral on most of the statements in similarities domain compared to the older age group. This could be possibly due to the younger respondents had relatively shorter history of medical illnesses and they were only started their follow up in hospital after the implementation of generic medicines policy, thus they were unsure about the differences between generic drugs and branded drugs. In terms of gender, this study showed that male participants believed that treatment with generic antibiotics were less efficacious compared to branded antibiotics. This might be related to personal experience. On the other hand, degree holders agreed that generic medicines had the same effect as branded medicines due to their greater acceptance in the information they were given
101 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 regarding generic or branded medicines. Greater acceptance means that they were less bias in supporting generic medicines or branded medicines alone. There were few limitations in our study. Firstly, convenient sampling was used in the study due to the busy setting in the outpatient pharmacy of Sibu Hospital. Also, the study team was unable to recruit the expected sample size of 170 subjects due to the poor response rate. However, this may not affect the outcome of the study as the minimum sample size of 139 was still achieved. In view of the above limitations, our results may not be generalised to the general population of Sibu.
Conclusion This study suggested that the knowledge about generic medicines among the patients who attended Sibu Hospital outpatient pharmacy was high. These patients had mixed perception on the efficacy of generic medicines but were neutral on the similarities of generic medicines. Age, gender, ethnicity, education level and knowledge about generic medicines were shown to be affecting the respondents’ perception on generic medicines.
Acknowledgements We would like to thank the Director General of Health, Ministry of Health of Malaysia for his permission to conduct this study and publish this article. Besides that, we would also like to acknowledge the Director, Head of Department of Pharmacy and Clinical Research Centre of Sibu Hospital for their advice. Also, we would like to thank Mr. Wong Zi Yen for the permission to use the validated Malay version of GMS questionnaire. Last but not least, we would like to thank all the respondents who answered the questionnaires and all the colleagues in the Department of Pharmacy who helped us in the recruitment of respondents.
Conflict of Interest Statement No external funding was received and the authors declared no conflict of interest.
References 1. Facts about Generic drug [Online] 2016. http://www.fda.gov/Drugs/ResourcesFor You/Consumers/BuyingUsingMedicineSafely/UnderstandingGenericDrugs/ucm167991.htm (accessed April 30, 2016). 2. Reducing Malaysian healthcare costs via generic drugs [Online] 2016 Apr 30. http://today.mims.com/topic/reducing-malaysianhealthcare-costs-via-generic-drugs (accessed October 6, 2016). 3. Wong, Z.Y.; Hassali, M.A.; Alrasheedy, A.A.; Saleem, F.; Yahaya, A.H.; Aljadhey, H. Patients’ beliefs about generic medicines in Malaysia. Pharmacy Practice. 2014, 12(4), 474. 4. Alrasheedy, A.A.; Hassali, M.A.; Kong, D.C.M.; Aljadhey, H.; Mohammed, I.; Al-Tamimi, S.K. Patient knowledge, perceptions, and acceptance of generic medicines: a comprehensive review of the current literature. Patient Intelligence. 2014, 6, 1-29. 102 5. Colgan, S.; Faasse, K.; Martin, L.R.; Stephens, M.H.; Grey, A.; Petrie, K.J. Perceptions of generic medication in the general population, doctors, and pharmacists: a systemic review. BMJ Open. 2015, 5:e008915. doi: 10.1136/bmjopen-2015-008915. 6. Shrank, W.H.; Cox, E.R.; Fischer, M.A.; Mehta, J.; Choudhry, N.K. Patients’ Perceptions of Generic Medications. Health Aff (Millwood). [Online] 2009, 8(2), 546-556. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748784/pdf/nihms110313.pdf (accessed October 11, 2017). 7. El-Dahyiat, F.; Kayyali, R. Evaluating patient’s perceptions regarding generic medicines in Jordan. J Pharm Policy Pract. [Online] 2013, 6(3). 8p. https://joppp.biomedcentral. com/track/pdf/10.1186/2052-3211-6-3. (accessed October 11, 2017). 8. Hakonsen, H.; Toverud, E.L. A review of patient perspectives on generics substitution: what are the challenges for optimal drug use. GaBIJournal. [Online] 2012, 1(1), 28-32. http://gabi-
102 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 journal.net/wp-content/uploads/GaBIJ-2012-1-p28-32-ReviewArticle-H%C3% A5konsen.pdf (accessed on October 11, 2017). 9. Wong, Z.Y.; Hassali, M.A.; Alrasheedy, A.A.; Saleem, F.; Yahaya, A.H.; Aljadhey, H. Translation and validation of the Malaysian version of generic medicines scale. J Med Mark. [Online] 2014, 14(1), 32-40. http://journals.sagepub.com/doi/pdf/10.1177/ 1745790414540928 (accessed on October 11, 2017). 10. Thomas, R.; Vitry, A. Consumer’s perception of generic medicines in community pharmacies in Malaysia. Southern Med Review. 2009, 2(2), 20-23. 11. Naing, L.; Winn, T.; Rusli, B.N. Practical Issues in Calculating the Sample Size for Prevalence Studies. Arch Orofac Sci. 2006, 1, 9-14. 12. Figueiras, M.J.; Alves, N.C.; Marcelino, D.; Cortes, M.A.; Weinman, J.; Horne, R. Assessing lay beliefs about generic medicines: Development of the generic medicines scales. Psychology, Health & Medicines. 2009, 14(3), 311-321. 13. Wong, Z.Y.; Hassali, M.A.; Saleem, F.; Yahaya, A.H.M.; Aljadhey, H. Translation and validation of the Malaysian version of generic medicines scale. J Med Mark. 2014, 14(1), 32-40. 14. Malaysian Census 2010-Population Distribution by Local Authority Areas and Mukims, 2010; Department of Statistics, Malaysia. [Online] 2010. http://www.statistics.gov.my/ portal/download_Population/files/population/03ringkasan_kawasan_PBT_Jadual1.pdf (accessed October 15, 2017). 15. Al-Gedadi, N.A.; Hassali, M.A.; Shafie, A.A. A pilot survey on perceptions and knowledge of generic medicines among consumers in Penang, Malaysia. Pharm Pract (Granada) [Online] 2008, 6(2), 93-97. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4141871/ (accessed October 15, 2017).
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103 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018
Assessment of Public Knowledge and Perception towards Childhood Vaccination in
Perlis, Malaysia
Wan Nor Amalina Zainun1, Nuwairoh Nasir1, Nur Iffah Iwani Ghazali1, Tan Keh Ying1
1 Tuanku Fauziah Hospital, Ministry of Health Malaysia
Abstract
Introduction: Childhood vaccination protects children from a variety of serious communicable diseases. In Malaysia, however, there are growing numbers of parents questioning the safety and necessity of routine childhood vaccination, hence refusing immunisation. This increases the risk of vaccine-preventable diseases. Objective: This study aimed to assess the knowledge and perception of the public towards childhood vaccination. Methods: A cross-sectional study was conducted from August to December 2017 in Perlis. Through convenience sampling, a validated questionnaire was distributed to Perlis citizens aged above 18 years old. The data was analysed using SPSS v20.0. Results: Of 387 participants included in the study, majority (n=229, 59.2%) of the respondents were female, university graduates (n=168, 43.4%), and Muslims (n=347, 89.7%). The results revealed that 65.1% (n=252) of the public had good knowledge while 65.6% (n=254) of the public had good perception towards childhood vaccination. Most of them obtained vaccination related information from the social network (n=62, 16%), healthcare provider (n=62, 16%) and television (n=58, 15%). There were significant associations between gender, age, educational background, occupation and income level with the knowledge and perception towards vaccination. Conclusion: The study showed that citizen in Perlis has good knowledge and perception on childhood vaccination. Female, as well as those with higher income and higher educational level, have better knowledge and perception towards childhood vaccination. Educational interventions should be focused on lower income group of the society in improving the public’s knowledge and perception on the childhood vaccination.
Keywords: knowledge, perception, childhood, vaccination
NMRR ID: NMRR-17-2641-37868
Corresponding author: 104 Wan Nor Amalina Zainun Pharmacy Department, Hospital Tuanku Fauziah, Jalan Kolam, 01000 Kangar, Perlis Email: [email protected]
104 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 Introduction Vaccination is the process which a person is made immune or resistant to an infectious disease, typically by administering vaccine1. Vaccine is a biological preparation that contains an agent that mimics a disease-causing organism, and it is often made up of weakened or killed forms of microbe, its toxins or one of its surface protein2. Vaccine has greatly reduced the burden of infectious disease3. It can prevent illness, disability, and death from vaccine-preventable diseases such as cervical cancer, diphtheria, hepatitis B, measles, mumps, pertussis (whooping cough), pneumonia, polio, rotavirus diarrhoea, rubella and tetanus4. The World Health Organization (WHO) has established the Expanded Programme on Immunization (EPI) to develop and expand immunisation programmes throughout the world5. In Malaysia, the National Immunisation Programme (NIP) was introduced in the early 1950s in accordance to the WHO EPI. Under the NIP initiatives, immunisation against several vaccine- preventable diseases is provided for all Malaysian children at certain ages without any charges6. Based on the Ministry of Health Malaysia’s vaccination schedule, children aged 12 months are recommended to receive eight basic primary immunisation: BCG, Hepatitis Dose 1 and 3, Diphtheria- Tetanus-Pertussis-Haemophilus Influenza Dose 1, 2 and 3, and Measles-Mumps-Rubella7. For past decades, Malaysia has achieved high immunisation coverage among infants and young children8. However, there is an increasing trend of vaccine hesitancy. The official statistics showed that the number of parents refusing to immunise their children had gone up from 470 in 2013 to 1,292 in 20159. Parental understanding of the importance of vaccination and their willingness to vaccinate their children plays a vital role in achieving complete immunisation for their children10. It is important to maintain 92% to 95% of vaccination coverage among the population in order to sustain herd immunity and to protect those who are unvaccinated and susceptible11. Towards this mission, not only parents’ understanding is important to maintain complete immunisation, public awareness also plays a role. Therefore, this study was carried out to assess the knowledge and perception of the public regarding childhood vaccination in Perlis.
Methods A cross-sectional study was conducted during a period of seven months (August 2017 to February 2018) in Perlis. The people of Perlis aged 18 years old and above were invited to answer the validated questionnaires developed by the Perlis State Hospital (Tuanku Fauziah Hospital). Sample size was calculated by Raosoft® software using the current Perlis population data of 251,500 acquired from the Department of Statistics Malaysia. The respondents were recruited through convenience sampling from various public places throughout Perlis. The questionnaire consisted of four sections, namely demographic data, knowledge, perception and knowledge seeking behaviour. Total knowledge and perception scores were computed and the mean value was identified (eight out of 13 and eight out of 14, respectively). Scores below the mean value was considered as having “poor knowledge” and “negative perception” whereas those 105 above the mean value were considered as having “sufficient knowledge” and “good perception” respectively. Data were analysed using Statistical Package for Social Sciences (SPSS) version 20. Chi- square test was used to investigate the association between knowledge and perception towards childhood vaccination. A p-value less than 0.05 was considered statistically significant. Mutivariable logistic regression model was applied to determine the factors associated with knowledge and perception towards childhood vaccination. The independent variables included age, gender, race, religion, location of residence, educational background, occupation, income, marital status and number of children.
105 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 Results Demographic data A total of 450 questionnaires were successfully distributed during the study period, and 387 respondents participated in the study. Their baseline characteristics were in Table 1. Majority of them were female (59.2%), Muslim (89.7%), Malay (88.6%) and aged greater than 25 years old (55.8%). The percentage of respondents living in rural and urban area was almost equal which were 50.4% and 49.6% respectively. Most of them had degree / Master / Ph.D. educational background (43.4%) followed by Diploma / STPM (26.6%).
Knowledge of public on childhood vaccination Overall, 65.1% (n=252) of the public had good knowledge on childhood vaccination and the knowledge was good across majority of the demographic characteristics (Table 2). Based on the univariate analyses, knowledge on childhood vaccination was associated with gender, educational level, occupational sector and monthly income. The knowledge was not influenced by respondents’ age, religion, race, location of residence, marital status and number of children. After adjusting for gender, educational level, occupational sector and monthly income in the multivariate model, only monthly income remained significantly associated with the level of childhood vaccination knowledge. Individuals with monthly income of RM3,000 – RM3,999 was 4 times more likely to have good knowledge compared to other monthly income groups (adjusted odds ratio (OR) 4.12, 95% confidence interval (CI) 1.7 – 10.0).
Perception of public towards childhood vaccination The results showed that 65.6% (n=254) of the public had good perception towards childhood vaccination. Female respondents expressed a better perception towards childhood vaccination compared to male (p=0.001) as demonstrated in Table 3. In terms of age, the highest rate of good perception was reported among respondents aged greater than 25 years old (74%) compared to those below 25 years old (56%, p<0.005). Civil servants were more likely to have good perception towards childhood vaccination compared to private employees (p<0.001). Respondents with monthly income of RM4,000 – RM5,000 had the highest rate of good perception towards childhood vaccination (86%), followed by those earning more than RM5,000 (80%) and RM3,000 – RM3,999 (71%). Further logistic regression analysis found that only two factors, i.e. gender and monthly income, were significantly associated with good perception towards childhood vaccination.
Knowledge Seeking Behaviour There were three sections in the questionnaire about knowledge seeking behaviour, namely the source of vaccine information, information the respondents want to know and their opinion regarding the best way for public to get the information (Table 4). From the results, most of the respondents thought social network (16%) and healthcare providers (16%) as the main source to obtain vaccine 106 information, followed by television (15%), family and friends (13%) and medical websites (13%). In Section 2, 18.1% of them wanted to know more about the advantages and disadvantages of childhood vaccination, 13.7% on halal status and contents of vaccine, and another 5.7% of respondents want to know type of vaccine and availability of vaccine in MOH facilities. Most of the respondents also believed that social media, mass media and digital media is the best way for public to get vaccine information (60%) followed by awareness programmes conducted by government and non- government association such as campaign, health talk and exhibition (30%).
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Table 1: Demographic data (N=387) Demographic data n (%) Age 25 years old 171 (44.2) ≥26 years old 216 (55.8) Gender Male 158 (40.8) Female 229 (59.2) Religion Muslim 347 (89.7) Non-Muslim* 40 (10.3) Race Malay 343 (88.6) Non-Malay** 44 (11.4) Location of residence Rural 195 (50.4) Urban 192 (49.6) Educational background UPSR / PMR# 26 (6.7) SPM / Matriculation 90 (23.3) Diploma / STPM 103 (26.6) Degree / Master / PhD 168 (43.4) Occupation Public sector 165 (42.6) Private sector 222 (57.4) Income None 116 (30) < RM2,000 89 (23) RM2,000 – RM2,999 45 (11.6) RM3,000 – RM3,999 48 (12.4) RM4,000 – RM5,000 50 (12.9) > RM5,000 39 (10.1) Marital Status Non-married## 180 (46.5) Married 207 (53.5) Children 107 Yes 178 (46) No 209 (54) * Non-Muslims comprised of Buddhism, Hindu, Christian and others ** Non-Malay comprised of Chinese, Indian and others # UPSR / PMR comprised of no formal education; UPSR and PMR ## Non-married comprised of single, divorced, widow and widower
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Table 2: Knowledge of public on childhood vaccination Knowledge Simple logistic regression Multiple logistic regression Demographic data Good Poor Crude OR 95% CI p-value Adjusted OR 95% CI p-value* n % n % Age 0.450 ≤ 25 years old 102 59.6 69 40.4 1 ≥ 26 years old 150 69.4 66 30.6 1.54 1.01, 2.34 Gender 0.003 Male 89 56.3 69 43.7 1 Female 163 71.2 66 28.8 1.92 1.25, 2.93 Religion 0.288 Muslim 229 66.0 118 34.0 1.43 0.74, 2.79 Non-Muslim 23 57.5 17 42.5 1 Race 0.222 Malay 227 66.2 116 33.8 1.49 0.78, 2.81 Non-Malay 25 56.8 19 43.2 1 Location of residence 0.526 Rural area 124 63.6 71 36.4 0.87 0.58, 1.33 Urban area 128 66.7 64 33.3 1 Educational level 0.001 Primary education 13 50 13 50 1 Secondary education 49 54.4 41 45.6 1.20 0.50, 2.86 Tertiary education 63 61.2 40 38.8 1.58 0.66, 3.74 Higher education 127 75.6 41 24.4 3.1 1.33, 7.22 Occupation <0.001 Government sector 127 77.0 38 23.0 2.59 1.66, 4.06 Private sector 125 56.3 97 43.7 1 Income <0.001 <0.001 None 66 56.9 50 43.1 1 1
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Table 3: Perception of public on childhood vaccination Perception Simple logistic regression Multiple logistic regression Demographic data Good Poor Crude OR 95% CI) p-value Adjusted OR (95% CI) p-value* n % n % Age <0.005 ≤ 25 years old 95 55.6 76 44.4 1 ≥ 26 years old 159 73.6 57 26.4 2.23 1.46, 3.42 Gender 0.001 <0.005 Male 89 56.3 69 43.7 1 Female 165 72.1 64 27.9 2.00 1.30, 3.06 1.95 (1.25,3.05) Religion 0.336 Muslim 225 64.5 122 35.2 0.70 0.34, 1.45 Non-Muslim 29 72.5 11 27.5 1 Race 0.295 Malay 222 64.7 121 35.3 1 Non-Malay 32 72.7 12 27.3 1.45 0.72, 2.93 Location of residence 0.519 Rural area 131 67.2 64 32.8 1.15 0.76, 1.75 Urban area 123 64.1 69 35.9 1 Educational level 0.027 Primary education 17 65.4 9 34.6 1 Secondary education 53 35.9 37 41.1 0.76 0.31, 1.89 Tertiary education 60 58.3 43 41.7 0.74 0.30, 1.81 Higher education 124 73.8 44 26.2 1.49 0.62, 3.59 Occupation <0.005 Government sector 125 75.8 40 24.2 2.25 1.44, 3.51 Private sector 129 58.1 93 41.9 1 Income <0.005 <0.005 None 56 48.3 60 51.7 1
109 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 Table 4: Knowledge seeking behaviour Criteria n (%)
Section 1: Source of vaccine information
Social network 62 (16) Healthcare provider 62 (16) Television 58 (15) Family and friends 50 (13) Medical websites 50 (13) Newspaper 43 (11) Magazine 31 (8) Radio 27 (7) Section 2: Information the respondents want to know
Advantages & disadvantages of childhood vaccination 70 (18.1) Halal status & contents of the vaccine 53 (13.7) Side effects of the vaccines 29 (7.5) Types and availability of vaccine in the MOH facilities 22 (5.7) Cost spent on vaccines 12 (3.1) Vaccination schedule and the use of vaccine 5 (1.3) Others 28 (7.2) Section 3: Opinion regarding the best way for public to get information on vaccines Social media, mass media and digital media 232 (60) Campaign, health talk, and exhibition 116 (30) Healthcare providers 27 (7) Formal education 4 (1)
Discussion Knowledge can be defined as the state of knowing about or being familiar with something12. Our study found that more than half (65%) of the respondents have good knowledge regarding childhood vaccination (N= 254). Approximately 92% of the respondents answered correctly that vaccine is important for protection against certain infectious disease and it can help the body fight certain infections, meanwhile 79.1% correctly answered that vaccination reduced incidence of certain infectious disease. In terms of knowledge on childhood vaccination, our study found that female respondents were 1.92 times more likely to have better knowledge compared to men. Women have better knowledge as they are usually the one that has greater decision making in child’s health13,14. In addition, socioeconomic status can affect vaccination knowledge level. Our study showed that there were significant differences in the level of immunisation knowledge among respondents of different 110 educational backgrounds and monthly income levels. Respondents from the lower educational background or lower monthly income groups had poorer knowledge compared to those with higher education and monthly income level. The same trend had been observed in the previous study10,15,16. Educational interventions should be focused on lower income group of the society in improving the public’s knowledge and perception on the childhood vaccination. Perception is a belief or opinion, often held by many people and based on how things seem. According to our study, female respondents were two times more likely to have positive perception towards vaccination compared to male. Gender refers to socially constructed roles, behaviours, activities and attributes that a given society considers appropriate for men and women13. The results of a qualitative study that explored teenagers’ understandings of and attitudes towards vaccines and
110 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 vaccine-preventable diseases showed that female participants were most aware of human papillomavirus (HPV) infection, although it was subject to misunderstandings, while male respondents commonly believed that it only affects female respondents17. Another study done by A. Raja’a et al. in 2002 on the coverage and perceptions of Medical Sciences students towards hepatitis B virus vaccine in Sana’a City, Yemen also revealed that the attitudes and practices of female students were better than that of males18. Women are usually the primary responsible person to deal with health-related issues. Immunisation interventions targeting only women, however, clearly neglect the critical influence that men have over women’s decision-making power. In many developing countries, women may have the primary responsibility for children’s healthcare but it is the men who have control over women’s access to health information and services, finances, transportation and other resources. In this study, we also found that higher income respondents had a good perception compared to lower income respondents. A study assessing the predictive effects of socioeconomic factors on influenza vaccination coverage rates in eleven European countries found that household income may significantly contribute to the chances of getting immunised against influenza19. In another study, low income families were less likely to receive needed health information regarding HPV vaccine, thereby reducing the likelihood of vaccine uptake20. Further analyses by the author revealed that lower income families had lower odds of receiving healthcare professionals’ recommendations after controlling other healthcare related factors such as insurance status, annual preventive care and usual source of care. Based on our findings, more respondents tended to obtain information from the social network and healthcare provider, followed by television and family or friends. The same trend was also observed in other studies1,10. Public that tended to use social media as the primary source of information could be vulnerable to misinformation. Information of vaccination found on website or social networks were sometimes inaccurate or having negative contents21. From the respondents’ point of view, mass media was the best channel to provide information to public. A study conducted by Pew Research Centre reported that 61% of American adults search for health information online and these information had impact on the health decisions in 60% of e-patients (internet user that search for health information online)24. Public tends to use online social media to obtain information, share stories and discuss health related concerns25. Another study conducted by Scanfeld et al. found that Twitter can be used as a method of informal sharing of health information26. However, the readers should be vigilant in browsing all these social media pages. Most of the respondents were concerned about the advantages and disadvantages of childhood vaccination, the halal status, and side effects of vaccination. This was also seen in a study conducted in Malaysia by Lim et al. and Azizi et al.22. It was evident that halal issue remained the main concern as the majority of Malaysians are Muslims. Research and development in Malaysia focus on producing bovine based vaccine and halal certified ingredients. However, it should be noted that the Islamic Religious authorities in Malaysia have issued fatwa or Islamic policy clarifying that porcine based medications, including vaccines, can be used in “dharurah” or emergency situations23. In this study, we encountered a number of practical difficulties. One of the challenges was the 111 difficulty to recruit the public. Most of them were in a rush when approached by the investigators to answer our questionnaires and it required approximately 20 minutes to answer all the questions. Some of the respondents also complained that the questions were difficult. This constraint contributed to the fact that a limited number of completed questionnaires were received. The length of the questionnaire presented was also a limitation and a lack of interest was observed in some respondents who participated in the study. As the questionnaire was in printed-version, geographical limitation was another difficulty in the execution of the study as the distribution of questionnaires could not cover all areas in Perlis. A similar study can be conducted with larger sample size, so that one may be able to obtain diverse demographic information when comparing results. Similar studies can
111 PHARMACY RESEARCH REPORTS | VOLUME 1 | 2018 be conducted by exploring the knowledge and perception of public towards vaccination at another location.
Conclusion This study showed that citizens in Perlis had good knowledge and perception on childhood vaccination. Female population and those with higher educational and income level had better knowledge towards childhood vaccination. Female and those with higher income level had a better perception towards childhood vaccination. Educational interventions may be targeted at the lower income groups of the society in improving the public’s knowledge and perception on the childhood vaccination.
Acknowledgements We would like to express our sincere gratitude to our research supervisor Mr. Mohamad Syafuan Fadzil and Ms. Umairah Abu Hassan for providing invaluable guidance throughout this research. We thank the management of Department of Pharmacy, Hospital Tuanku Fauziah for their support in this work. We would like to thank the Director General of Health for his permission to publish this article. Finally, our thanks go to all that have supported us directly or indirectly throughout this research work.
Conflict of Interest Statement No external funding was received and the authors declared no conflict of interest.
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